Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers

ABSTRACT

This invention relates to novel compounds. The compounds of the invention are kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Raf kinases, e.g., B-Raf and C-Raf. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Raf kinases, for example, cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.

RELATED APPLICATIONS

This application is a § 371 national stage application based on PatentCooperation Treaty Application serial number PCT/GB2015/052640, filedSep. 11, 2015, which claims the benefit of priority to GB 1416186.3,filed Sep. 12, 2014.

This invention relates to compounds. More specifically, the inventionrelates to compounds useful as kinase inhibitors, for example RAFkinases such as B-RAF and C-RAF. In addition the invention contemplatesprocesses to prepare the compounds and uses of the compounds.

BACKGROUND

Kinases are a class of enzyme that control the transfer of phosphategroups from phosphate donors, for example ATP, to specific substrates.Protein kinases are a subset of kinases and serine/threonine-proteinkinase B-RAF is one such protein kinase. Serine/threonine-protein kinaseB-RAF is more commonly known as B-RAF and throughout this applicationthese two terms will be used interchangeably.

B-RAF is a member of the RAF kinase family, the other members of thefamily being A-RAF and C-RAF. Each of the RAF kinases is aserine/threonine-specific protein kinase, an enzyme that phosphorylatesthe hydroxyl group of serine or threonine residues within a protein. TheRAF kinases are involved in the mitogen-activated protein kinase (MAPK)cascade, a key pathway involved in internal cell signalling responsiblefor cell division, cell proliferation, programmed cell death(apoptosis), cell differentiation, and embryonic development.

Defects in the MAPK pathway can affect the signalling within a cell andcan lead to uncontrolled cell growth through deviant cell division andirregular cell death. Such defects in the MAPK pathway can be caused bymutations to the RAF kinases or aberrant expression of the RAF kinases,as such abnormalities associated with the RAF kinases, such as the knownmutation B-RAF^(V600E) can give rise to uncontrolled cell growth andconsequently cancer.

Thus, controlling aberrant functioning of RAF kinases by small moleculeinhibition presents a useful approach for the treatment of cancers.

A number of RAF inhibitors have been identified. Two such compounds aredabrafenib and vemurafenib. Dabrafenib is a B-RAF inhibitor indicated inthe treatment of malignant melanoma and marketed by GlaxoSmithKline.Dabrafenib was approved for the treatment of malignant melanoma in May2013 by the US FDA. Similarly, in August 2011 vemurafenib was approvedfor the treatment of melanoma by the US FDA. As with dabrafenib,vemurafenib is a B-RAF inhibitor, specifically of the B-RAF^(V600E)mutation.

RAF inhibitors such as dabrafenib and vemurafenib have been approved forthe treatment of unresectable and metastatic B-RAF-mutant melanoma, butthese agents lack efficacy in B-RAF-mutant colorectal cancer (CRC),partly because of EGFR-mediated feedback reactivation of the MAPKpathway. Furthermore, RAF inhibitor treatment of RAS-mutant,B-RAF^(WT)-melanomas has been associated with other skin cancers, suchas cutaneous squamous cell carcinoma due to MAPK pathway paradoxicalactivation. There is therefore a clinical need for novel agentstargeting the MAPK pathway that do not have the undesirable propertiesof EGFR-mediated feedback reactivation of the MAPK pathway and MAPKpathway paradoxical activation.

A number of patents have been published describing B-RAF inhibitors. Onesuch publication is WO 2012/125981 which describes a compound having astructure related to dabrafenib. Both compounds contain a central5-membered heterocycle flanked by two substituted 6-membered (or higher)ring systems. In addition to WO 2012/125981, B-RAF inhibitors have alsobeen disclosed in WO 2012/016993, WO 2011/085269, WO 2011/025927, WO2011/092088 and WO 2011/023773, for example.

In addition to these documents fused tricyclic compounds as RAF kinaseinhibitors were recently disclosed in WO 2013/097224. In addition, US2010/0197924 discloses aminotetralin compounds with kinase inhibitoryactivity, specifically RAF kinase inhibitory activity and WO 2007/067444discloses bicyclic compounds for the same purpose.

It is an aim of certain embodiments of this invention to provide newcancer treatments. In particular, it is an aim of certain embodiments ofthis invention to provide compounds which have comparable activity toexisting cancer treatments, ideally better activity.

Certain embodiments of this invention aim to provide for compounds whichare suitable for the treatment of cancers which have been identified ascontaining a mutation of the BRAF kinase, for example human melanomas,thyroid cancer, Barret's adenocarcinoma, biliary tract carcinomas,breast cancer, cervical cancer, cholangiocarcinoma, central nervoussystem tumors, glioblastomas, astrocytomas, ependymomas, colorectalcancer, large intestine colon cancer, gastric cancer, carcinoma of thehead and neck, hematologic cancers, leukaemia, acute lymphoblasticleukaemia, myelodysplastic syndromes, chronic myelogenous leukaemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukaemia,multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer,pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer,sarcoma, uveal melanoma and skin cancer. Certain embodiments of thisinvention aim to provide for compounds which are suitable for thetreatment of cancers which have been identified as containing theBRAF^(V600E) mutation. For example BRAF^(V600E) melanoma, BRAF^(V600)Ecolorectal cancer, BRAF^(V600E) papillary thyroid cancers, BRAF^(V600E)low grade serous ovarian cancers, BRAF^(V600E) glioma, BRAF^(V600E)hepatobiliary cancers, BRAF^(V600E) hairy cell leukaemia, BRAF^(V600E)non-small cell cancer, and BRAF^(V600E) pilocytic astrocytoma.

RAF inhibitor treatment of RAS-mutant, BRAF^(WT)-melanomas has beenassociated with other skin cancers, such as cutaneous squamous cellcarcinoma due to MAPK pathway paradoxical activation. There is thereforea clinical need for novel agents targeting the MAPK pathway that do nothave these undesirable properties. Certain embodiments of this inventionaim to provide compounds which show reduced side effects. For example,certain embodiments of this invention aim to provide for compounds whichshow reduced paradoxical activation of the MAPK pathway in BRAF^(WT)cells and which inhibit the MAPK pathway at therapeutically relevantconcentrations.

Certain embodiments of this invention aim to provide for compounds whichshow sustained MAPK pathway inhibition over 24 hours in cell lines knownto undergo reactivation of the MAPK pathway following treatment with theRAF inhibitors dabrafenib and vemurafenib. Certainembodiments also aimto reduce paradoxical activation of MAPK pathway compared to dabrafeniband/or vemurafenib.

It is an aim of certain embodiments of this invention to providecompounds which exhibit reduced cytotoxicity relative to prior artcompounds and existing therapies.

Another aim of certain embodiments of this invention is to providecompounds having a convenient pharmacokinetic profile and a suitableduration of action following dosing. A further aim of certainembodiments of this invention is to provide compounds in which themetabolised fragment or fragments of the drug after absorption are GRAS(Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of theabove aims.

BRIEF SUMMARY OF THE DISCLOSURE

In an aspect of the invention there is provided a compound of formula(I):

wherein:A is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl orthiophenyl ring which is substituted or unsubstituted, and whensubstituted A contains 1 to 3 substituents independently selected from:halo, ═O, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, —OR^(A),—NR^(A)R^(B), SO₂R^(A) and SOR^(A);R¹ is a substituted or unsubstituted heterocyclic moiety which eithercontains 5 or 6 atoms in a single ring or 8, 9, 10 or 11 atoms in afused bicyclic ring system, when substituted R¹ contains 1 to 4substituents independently selected from: halo, —OR^(A), —NR^(A)R^(B),═O, —OC(O)R^(C), —C(O)R^(C), —C(O)OR^(A), —NR^(A)C(O)R^(C),—C(O)NR^(A)R^(B), —SO₂R^(C), —SOR^(C), —NR^(A)SO₂R^(C), —SO₂NR^(A)R^(B),—CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₅ cycloalkyl;X is N, O or S;Y is —CR^(2B)W or —CW;W represents: -het¹-R³ or -het², in which het¹ is a five or six memberedcarbocyclic ring or heterocyclic ring, and het² is a carbocyclic orheterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclicring system; and in which each of het¹ and het² may be independentlyunsubstituted or substituted and contain 1 or 2 substituentsindependently selected at each occurrence from: halo, —OR^(A), —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, in which the aforementionedalkyl, haloalkyl and cycloalkyl groups may themselves also beunsubstituted or substituted with 1 to 3 groups independently selectedfrom: —OR^(A), —CN, —NR^(A)R^(B);Z is N, O, S, —CR^(2C), —CR^(2C)R^(2D);

R^(2A), R^(2B), R^(2C) and R^(2D) are each independently selected ateach occurrence from: H, halo, —OR^(A), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₃₋₆ cycloalkyl;

R³ is selected from substituted or unsubstituted: C₁₋₆ alkyl, C₁₋₆haloalkyl, a carbocyclic moiety or a heterocyclic moiety, wherein thecarbocyclic moiety and heterocyclic moiety either contain 5 or 6 atomsin a single ring or 8, 9 or 10 atoms in a fused bicyclic ring system,and when substituted R³ contains 1 to 4 substituents independentlyselected from: halo, —OR^(A), —NR^(A)R^(B), —SO₂R^(C), —SOR^(C), —CN,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl in which the aforementionedalkyl, haloalkyl and cycloalkyl groups may themselves also beunsubstituted or substituted with 1 to 3 groups independently selectedfrom: —OR^(A), —CN, —SOR^(C), and —NR^(A)R^(B);R^(A) and R^(B) are each independently selected from H, C₁₋₄ alkyl andC₁₋₄ haloalkyl; andR^(C) is selected from C₁₋₄ alkyl and C₁₋₄ haloalkyl.

The present invention provides pharmaceutically acceptable salts ofcompounds of formula (I) and all other formulae disclosed herein.

Het¹ may be a five or six membered cycloalkyl or heterocyclic ring, andhet² may be a carbocyclic or heterocyclic ring system containing 8, 9 or10 atoms in a fused bicyclic ring system Preferably, het¹ is a five orsix membered heterocyclic ring and het² is a heterocyclic ring systemcontaining 8, 9 or 10 atoms in a fused bicyclic ring system.

Ring A is fused to the ring containing X, Y and Z. The two fused ringsshare two carbon atoms at the point of fusion, as would be understood bythe person skilled in the art.

In embodiments the compound of formula (I) is a compound according toformula (Ia)

wherein A¹, A² and A³ are each independently selected from CR⁴ or N, andR⁴ is independently selected at each occurrence from: halo, —OR^(A),—NR^(A)R^(B), ═O, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl.

In preferred embodiments A is phenyl. Thus, in an embodiment, there isprovided a compound of formula (II):

In preferred embodiments, there is provided a compound of formula (IIa):

In embodiments X is O or S. Preferably, X is O.

In certain embodiments Z is O, CR^(2C) or CR^(2C)R^(2D). In certainembodiments Z is O and Y is CR^(2B)W. In certain embodiments Z isCR^(2C)R^(2D) and Y is CR^(2B)W. In certain embodiments Z is CR^(2C) andY is CW.

In certain embodiments X is O, Z is CR^(2C)R^(2D) and Y is CR^(2B)W.Thus, there is provided a compound according to formula (IIIa):

In certain embodiments X is O, Z is CR^(2C) and Y is CW. Thus, there isprovided a compound according to formula (IIIb):

In certain embodiments X is O, Z is O and Y is CR^(2B)W. Thus, there isprovided a compound according to formula (IIIc):

In certain embodiments the compound of formulae (IIIa) and (IIIc) may besingle enantiomers. For example, compounds of formula (IIIa) may becompounds of formula (IId) or (IIIe) and compounds of formula (IIIc) maybe compounds of formula (IIIf) and (IIIg):

The central bicyclic ring system of the compound of formula (IIIa) is achromane ring. The central bicyclic ring system of the compound offormula (IIIb) is a chromene ring. The central bicyclic ring system ofthe compound of formula (IIIc) is a dihydrobenzodioxine ring. Each ofthe central bicyclic ring systems are substituted with —O—R¹. The atomsof each of the central bicyclic groups are numbered as illustratedbelow.

The —O—R¹ substituent on the chromane, chromene or dihydrobenzodioxineof formulae (IIIa), (IIIb) and (IIIc) respectively may be substituted atpositions 5, 6, 7, or 8. Preferably —O—R¹ is substituted at position 6.When —OR¹ is substituted at position 6 of the chromane, chromene ordihydrobenzodioxine of formulae (IIIa), (IIIb) and (IIIc) respectivelythere is provided a compound of formulae (IVa), (IVb) and (IVc):

In an embodiment the compounds of the invention are single enantiomers.Thus, as indicated below, the compounds of the present invention may bea compound of formulae (IVd), (IVe), (IVf) or (IVg):

In a preferred embodiment R^(2A), R^(2B), R^(2C) and R^(2D) are each H.It is particularly preferred that R^(2A), R^(2B), R^(2C) and R^(2D) areeach H in the compounds of formulae (IVa), (IVb), (IVc), (IVd), (IVe),(IVf) and (IVg) as appropriate.

R¹ may be selected from substituted or unsubstituted: pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl,isoindolinyl, quinolinyl, tetrahydroquinolinyl, dihydroquinolinyl,quinolinone-yl, tetrahydroquinolinone-yl, dihydroquinolinone-yl,isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl,isoquinolinone-yl, tetrahydroisoquinolinone-yl,dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl,dihydronappthyridinyl, tetrahydronaphthyridinyl,oxotetrahydronaphthyridinyl, dihydropyrrolopyridinone (optionally a1,3-dihydropyrrolopyridinone) and oxo-dihydro-H-naphthyridinyl.Preferably, R¹ is substituted or unsubstituted pyridyl, substituted orunsubstituted oxo-dihydro-H-naphthyridinyl, or substituted orunsubstituted dihydropyrrolopyridinone (optionally a1,3-dihydropyrrolopyridinone). Further preferably, R¹ is methylpyridylor oxodihydro-H-naphthyridinyl.

In embodiments R¹ is a substituted or unsubstituted heterocyclic moietywhich either contains 6 atoms in a single ring or 10 atoms in a fusedbicyclic ring system. R¹ may be a substituted or unsubstitutedheterocyclic moiety, wherein the heterocyclic moiety is a 6 memberedaromatic ring or a fused bicyclic ring system that is unsaturated oraromatic containing 10 atoms. Optionally, the heterocyclic moietycontains 1, 2 or 3 heteroatoms selected from N, O or S. Preferably, theheterocyclic moiety contains 1 or 2 nitrogen atoms.

When R¹ is substituted it is preferably substituted with halo, —OR^(A),—NR^(A)R^(B), ═O, —OCN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —NR^(A)C(O)R^(C),—C(O)NR^(A)R^(B), —NR^(A)SO₂R^(C) or —SO₂NR^(A)R^(B). Preferably R¹ issubstituted with —NR^(A)C (O)R^(C), —C(O)NR^(A)R^(B), —NR^(A)SO₂R^(C) or—SO₂NR^(A)R^(B).

In preferred embodiments when R¹ is substituted it is preferablysubstituted with fluoro, chloro, —OH, —NH₂, —OMe, —NHMe, —NMe₂, ═O, —CN,methyl, trifluoromethyl, —NHC(O)Me, —NMeC(O)Me, —NHC(O)Et, —NMeC(O)Et,—C(O)NH₂, —C(O)NHMe, —C(O)NMe₂, —C(O)NHEt, —NHSO₂Me, —NMeSO₂Me, —SO₂NH₂,—SO₂NHMe, —SO₂NMe₂. Preferably R¹ is substituted with methyl or ═O.

R¹ may be selected from substituted or unsubstituted: pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, tetrahydroquinolinyl,dihydroquinolinyl, quinolinone-yl, tetrahydroquinolinone-yl,dihydroquinolinone-yl, isoquinolinyl, tetrahydroisoquinolinyl,dihydroisoquinolinyl, isoquinolinone-yl, tetrahydroisoquinolinone-yl,dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl,dihydronappthyridinyl, tetrahydronaphthyridinyl,oxotetrahydronaphthyridinyl, dihydropyrrolopyridinone (optionally a1,3-dihydropyrrolopyridinone), and oxo-dihydro-H-naphthyridinyl.Preferably, R¹ is substituted or unsubstituted pyridyl,dihydropyrrolopyridinone (optionally a 1,3-dihydropyrrolopyridinone) orsubstituted or unsubstituted oxo-dihydro-H-naphthyridinyl. Furtherpreferably, R¹ is methylpyridyl or oxo-dihydro-H-naphthyridinyl.

In an embodiment, there is provided a compound of formulae (I), (II),(III) or (IV) wherein R¹ is methylpyridyl oroxo-dihydro-H-naphthyridinyl. For example, there is provided a compoundof formula (IVa) wherein R¹ is methylpyridyl oroxo-dihydro-H-naphthyridinyl and R^(2A), R^(2B), R^(2C) and R^(2D) areeach H. Thus, in an embodiment there is provided a compound of formulae(Va) and (Vb):

Het¹ and het² may be substituted or unsubstituted. Het¹ and het² may notbe substituted with an oxo group, for example pyrollidinone is not ahet¹ group and purinone is not a het² group because the groups contain asubstiuted oxo group. In an embodiment het² is not purinone.

In embodiments, W represents -het¹-R³ or -het², wherein het¹ is asubstituted or unsubstituted five membered carbocyclic ring orheterocyclic ring, and

het² is a substituted or unsubstituted carbocyclic or heterocyclic ringsystem, containing 8, 9 or 10 atoms in a fused bicyclic ring system.

In embodiments, W represents -het¹-R³ or -het², wherein het¹ is asubstituted or unsubstituted five membered heterocyclic ring, and

het² is a substituted or unsubstituted heterocyclic ring system,containing 8, 9 or 10 atoms in a fused bicyclic ring system.

In embodiments, W represents -het¹-R³ or -het², wherein het¹ isrepresented by a group selected from substituted or unsubstituted: C₅₋₆cycloalkyl, C₆ aryl, C₅₋₆ heterocycloalkyl or C₅₋₈ heteroaryl, and

het² is represented by a group selected from substituted orunsubstituted C₈₋₁₀ cycloalkyl, C₁₀ aryl, C₈₋₁₀ heterocycloalkyl orC₈₋₁₀ heteroaryl.

In embodiments, W represents -het¹-R³ or -het², wherein het¹ isrepresented by a group selected from substituted or unsubstituted: C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl or C₅₋₆ heteroaryl, and

het² is represented by a group selected from substituted orunsubstituted C₈₋₁₀ cycloalkyl, C₁₀ aryl, C₈₋₁₀ heterocycloalkyl orC₈₋₁₀ heteroaryl.

Het¹ may be a five or six membered heterocyclic ring, and het² may be aheterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclicring system

Preferably, het¹ is represented by C₅₋₆ heteroaryl and het² isrepresented by C₈₋₁₀ heteroaryl. Further preferably, het¹ is representedby C₅ heteroaryl.

In any of the embodiments described herein het¹ may be a five memberedcarbocyclic ring or heterocyclic ring (preferably heterocyclic) which isunsubstituted or substituted and het² may be a 9 membered carbocyclic orheterocyclic bicyclic ring system (preferably heterocyclic) which isunsubstituted or substituted.

In embodiments het² may be a bicyclic ring system with one of the ringsof the bicyclic ring system being a five membered ring. Optionally, thefive membered ring may be bonded to the ring containing X, Y and Z, forexample the five membered ring may be bonded to the chromane, chromeneor dihydrobenzodioxine of formulae (IIIa), (IIIb) and (IIIc)respectively.

In embodiments het¹ and het² are unsubstituted.

Het¹ may be represented by substituted or unsubstituted: pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, oxadiazole, thiadiazole and triazole, and het² may berepresented by substituted or unsubstituted: indoline, isoindoline,benzodioxane, benzofurane, isobenzofurane, benzothiophene,isobenzothiophene, benzodioxolane, indazole, indazoline, benzimidazole,benzimidazoline, benzthiazole, benzoisothiazole, chromane, isochromane,tetraline, quinoline, isoquinoline, tetrahydroquinoline,tetrahydroisoquinoline and tetrahydroquinoxaline. Preferably, het¹ isrepresented by substituted or unsubstituted: pyrazole, imidazole oroxadiazole and het² is represented by substituted or unsubstitutedbenzimidazole.

In an embodiment there are provided compounds wherein W represents-het¹-R³ and het¹ is represented by substituted or unsubstituted:pyrazole, imidazole or oxadiazole. In an alternative embodiment thereare provided compounds wherein W represents -het² and het² isrepresented by substituted or unsubstituted benzimidazole.

In an embodiment there are provided compounds of formulae (IIIa), (IIIb)and (IIIc), wherein W represents -het¹-R³ and het¹ is represented bysubstituted or unsubstituted: pyrazole, imidazole or oxadiazole. In analternative embodiment there are provided compounds of formulae (Ilila),(IIIb) and (IIIc), wherein W represents -het² and het² is represented bysubstituted or unsubstituted benzimidazole.

In an embodiment there are provided compounds of formulae (IVa), (IVb)and (IVc), wherein W represents -het¹-R³ and het¹ is represented bysubstituted or unsubstituted: pyrazole, imidazole or oxadiazole. In analternative embodiment there are provided compounds of formulae (IVa),(IVb) and (IVc), wherein W represents -het² and het² is represented bysubstituted or unsubstituted benzimidazole.

In an embodiment the compounds according to formula (I) are compounds offormulae (VIa), (VIb), (VIc), (VId) or (VIe):

whereinm is selected from 0, 1 or 2; andR⁵ is independently selected at each occurrence from: halo, —OR^(A),C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl.

In an embodiment the compounds according to formula (I) are compounds offormulae (VIf), (VIg), (VIh), (VIi) or (VIj):

whereinm is selected from 0, 1 or 2; andR⁵ is independently selected at each occurrence from: halo, —OR^(A),C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl.

In an embodiment the compounds according to formula (I) are compounds offormulae (VIk), (VIm), (VIn), (VIo) or (VIp):

whereinm is selected from 0, 1 or 2; andR⁵ is independently selected at each occurrence from: halo, —OR^(A),C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl.

In an embodiment there is provided compounds of formulae (VIa), (VIb),(VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj) (VIk), (VIm),(VIn), (VIo) or (VIp).

In a preferred embodiment of the compounds of (VIa), (VIb), (VIc),(VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj) (VIk), (VIm), (VIn),(VIo) or (VIp), R^(2A), R^(2B), R^(2C) and R^(2D) (as appropriate) areeach H.

In an embodiment m is 0 or 1. In an embodiment R⁵ is halo, preferablychloro. In a preferred embodiment m is 0 or 1 and R⁵ is halo, preferablychloro.

In an embodiment, there are provided compounds of formulae (VIa), (VIb),(VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj) (VIk), (VIm),(VIn), (VIo) or (VIp), wherein R¹ is substituted or unsubstitutedpyridyl or substituted or unsubstituted oxo-dihydro-H-naphthyridinyl,preferably wherein R¹ is methylpyridyl or oxo-dihydro-H-naphthyridinyl.

In embodiments R³ is selected from: C₁₋₆ alkyl, a substituted orunsubstituted carbocyclic moiety or a substituted or unsubstitutedheterocyclic moiety, wherein the carbocyclic moiety and heterocyclicmoiety either contain 5 or 6 atoms in a single aromatic ring or 8, 9 or10 atoms in a fused bicyclic ring system, wherein one ring of thebicyclic ring system is aromatic.

R³ may be selected from a substituted or unsubstituted: iso-propyl,tert-butyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinylpyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,triazolyl, indolinyl, isoindolinyl, benzodioxanyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzodioxolanyl,indazolyl, indazolinyl, benzimidazolyl, benzimidazolinyl, benzthiazolyl,benzoisothiazol, chromanyl, isochromanyl, tetralinyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl andtetrahydroquinoxalinyl.

Preferably, R³ may be selected from: tert-butyl, phenyl, pyridyl,benzodioxanyl, benzofuranyl, benzodioxolanyl and thiophenyl.

When R³ is substituted it may contain 1 or 2 substituents. When R³ issubstituted it may contain 1 to 4 substituents independently selectedfrom: halo, —OR^(A), —NR^(A)R^(B), ═O, —OC(O)R^(C), —C(O)R^(C),—C(O)OR^(A), —NR^(A)C(O)R^(C), —C(O)NR^(A)R^(B), —SO₂R^(C), —SOR^(C),—CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalky in which theaforementionedalkyl, haloalkyl and cycloalkyl groups may themselves alsobe unsubstituted or substituted with 1 to 3 groups independentlyselected from: —OR^(A), —CN, —SOR^(C), and NR^(A)R^(B)I.

In embodiments R³ is substituted by 1 or 2 substituents selected from:chloro, fluoro, methyl, ethyl, —OMe, —CN, —SO₂Me, trifluoromethyl andtrifluoroethyl, in particular chloro, fluoro, methyl, ethyl, —SO₂Me,trifluoromethyl and trifluoroethyl.

In embodiments R^(A) and R^(B) are each independently selected from H,methyl, ethyl or trifluoromethyl and R^(C) is selected from methyl,ethyl or trifluoromethyl. Preferably, R^(A) and R^(B) are H; R^(A) andR^(B) are methyl; or R^(A) is H and R^(B) is methyl. Preferably, R^(C)is methyl.

Any compound of the invention may be a racemic mixture of twoenantiomers or a single enantiomer, either the (R)- or (S)-enantiomer.The compounds of the invention may also be a single enantiomer, eitherthe (+)- or (−)-enantiomer, as determined by the degree of rotation ofplane polarized light.

In particular, the invention provides the following compounds.

Some of the above compounds have a chiral centre. Both enantiomers ofthe above compounds are contemplated by the invention. The chiral centreis indicated on the compounds above with a * symbol. In one embodimentthe compounds of the invention have the (R)-configuration at thestereocentre. In an alternative embodiment the compounds of theinvention have the (S)-configuration at the stereocentre.

In another aspect of the invention there is provided a compound offormula (I) for use as a medicament.

In another aspect a compound of formula (I) is for use in the treatmentof a condition which is modulated by RAF kinases, for example B-RAF orC-RAF. Usually conditions that are modulated by RAF kinases, optionallyB-RAF or C-RAF, are conditions that would be treated by the inhibitionof RAF kinases, optionally B-RAF or C-RAF, using a compound of thepresent invention. A compound of formula (I) may be for use in thetreatment of a condition treatable by the inhibition of RAF kinases,optionally B-RAF or C-RAF.

RAF kinase inhibition is relevant for the treatment of many differentdiseases associated with the abnormal activity of the MAPK pathway. Inembodiments the condition treatable by the inhibition of RAF kinases,for example B-RAF or C-RAF, may be selected from: cancer, sarcoma,melanoma, skin cancer, haematological tumors, lymphoma, carcinoma andleukemia. Specific cancers, sarcomas, melanomas, skin cancers,haematological tumors, lymphomas, carcinomas and leukemia treatable bythe inhibition of RAF kinases, for example B-RAF or C-RAF, may beselected from: Barret's adenocarcinoma; biliary tract carcinomas; breastcancer; cervical cancer; cholangiocarcinoma; central nervous systemtumors; primary CNS tumors; glioblastomas, astrocytomas; glioblastomamultiforme; ependymomas; seconday CNS tumors (metastases to the centralnervous system of tumors originating outside of the central nervoussystem); brain tumors; brain metastases; colorectal cancer; largeintestinal colon carcinoma; gastric cancer; carcinoma of the head andneck; squamous cell carcinoma of the head and neck; acute lymphoblasticleukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes;chronic myelogenous leukemia; hairy cell leukaemia; Hodgkin's lymphoma;non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma;erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lungcancer; non-small cell lung cancer; ovarian cancer; endometrial cancer;pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer;metastatic melanoma; uveal melanoma; and papilliary thyroid cancers.

RAF kinases inhibition, for example B-RAF or C-RAF, may also be relevantto the treatment of cardio-facio cutaneous syndrome and polycystickidney disease.

In another aspect a compound of formula (I) is for use in the treatmentof a condition which is modulated by a mutant RAF kinase, for exampleB-RAF^(V600E). Usually conditionsthat are modulated by mutant RAFkinases, optionally B-RAF^(V600E), are conditions that would be treatedby the inhibition of mutant RAF kinases, optionally B-RAF^(V600E), usinga compound of the present invention. A compound of formula (I) may befor use in the treatment of a condition treatable by the inhibition ofmutant RAF kinases, optionally B-RAF^(V600E). In emboidiments thecondition treatable by the inhibition of mutant RAF kinases, for exampleB-RAF^(V600E), may be selected from: BRAF^(V600E) melanoma, BRAF^(V600E)colorectal cancer, BRAF^(V600E) papillary thyroid cancers, BRAF^(V600E)low grade serous ovarian cancers, BRAF^(V600E) glioma, BRAF^(V600E)hepatobiliary cancers, BRAF^(V600E) hairy cell leukaemia, BRAF^(V600E)non-small cell cancer, and BRAF^(V600E) pilocytic astrocytoma.

In an embodiment the conditions treatable by the inhibition of RAFkinases, for example B-RAF or C-RAF, may be selected from melanoma,non-small cell cancer, colorectal cancer, ovarian cancer, thyroidcancer, breast cancer and cholangiocarcinoma. In particular, thecondition treatable by the inhibition of RAF kinases, for example B-RAFor C-RAF, may be colorectal cancer or melanoma.

The invention contemplates methods of treating the above mentionedconditions and contemplates compounds of the invention for use in amethod of treatment of the above mentioned conditions

In an aspect of the invention, a compound of the invention may be foruse in the treatment of a condition selected from: cancer, sarcoma,melanoma, skin cancer, haematological tumors, lymphoma, carcinoma andleukemia. Specific cancers, sarcomas, melanomas, skin cancers,haematological tumors, lymphomas, carcinomas and leukemia that may betreated by the compound of the invention may be selected from: Barret'sadenocarcinoma; biliary tract carcinomas; breast cancer; cervicalcancer; cholangiocarcinoma; central nervous system tumors; primary CNStumors; glioblastomas, astrocytomas; glioblastoma multiforme;ependymomas; seconday CNS tumors (metastases to the central nervoussystem of tumors originating outside of the central nervous system);brain tumors; brain metastases; colorectal cancer; large intestinalcolon carcinoma; gastric cancer; carcinoma of the head and neck;squamous cell carcinoma of the head and neck; acute lymphoblasticleukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes;chronic myelogenous leukemia; hairy cell leukaemia; Hodgkin's lymphoma;non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma;erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lungcancer; non-small cell lung cancer; ovarian cancer; endometrial cancer;pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer;metastatic melanoma; uveal melanoma; and papilliary thyroid cancers.

In an embodiment a compound of the invention may be for use in thetreatment of a condition selected from: melanoma, non-small cell cancer,colorectal cancer, ovarian cancer, thyroid cancer, breast cancer andcholangiocarcinoma. In particular, the compound of the invention may befor use in the treatment of colorectal cancer or melanoma.

In an aspect of the invention there is provided a method of treatment ofa condition which is modulated by RAF kinases, wherein the methodcomprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof.

The method of treatment may be a method of treating a conditiontreatable by the inhibition of RAF kinases, e.g. B-RAF or C-RAF. Theseconditions are described above in relation to conditions treatable bythe inhibition of RAF kinases.

In an aspect of the invention there is provided a method of treatment ofa condition selected from: cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma and leukemia wherein themethod comprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof. Specific cancers, sarcomas,melanomas, skin cancers, haematological tumors, lymphomas, carcinomasand leukemia that may be treated by the method of treatment may beselected from: Barret's adenocarcinoma; biliary tract carcinomas; breastcancer; cervical cancer; cholangiocarcinoma; central nervous systemtumors; primary CNS tumors; glioblastomas, astrocytomas; glioblastomamultiforme; ependymomas; seconday CNS tumors (metastases to the centralnervous system of tumors originating outside of the central nervoussystem); brain tumors; brain metastases; colorectal cancer; largeintestinal colon carcinoma; gastric cancer; carcinoma of the head andneck; squamous cell carcinoma of the head and neck; acute lymphoblasticleukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes;chronic myelogenous leukemia; hairy cell leukaemia; Hodgkin's lymphoma;non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma;erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lungcancer; non-small cell lung cancer; ovarian cancer; endometrial cancer;pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer;metastatic melanoma; uveal melanoma; and papilliary thyroid cancers.

In an embodiment the method may be for treating a condition selectedfrom: melanoma, non-small cell cancer, colorectal cancer, ovariancancer, thyroid cancer, breast cancer and cholangiocarcinoma, whereinthe method comprises administering a therapeutic amount of a compound ofthe invention to a patient in need thereof. In particular, method may befor treating colorectal cancer or melanoma.

In another aspect of the invention there is provided a pharmaceuticalcomposition, wherein the composition comprises a compound of theinvention and one or more pharmaceutically acceptable excipients.

In an embodiment the pharmaceutical composition may be a combinationproduct comprising an additional pharmaceutically active agent. Theadditional pharmaceutically active agent may be an anti-tumor agentdescribed below.

In an aspect of the invention there is provided a use of a compound offormula (I) in the manufacture of a medicament for the treatment of acondition which is modulated by RAF kinases, e.g. B-RAF or C-RAF. Thecondition may be any of the conditions mentioned above.

In any of the aspects or embodiments of the invention the RAF kinasesmay be B-RAF or C-RAF. In any of the aspects or embodiments of theinvention the B-RAF kinase may be the B-RAF V600E mutant. Thus, thecompounds of the invention may be utilised in the treatment of acondition which is modulated by B-RAF and/or C-RAF. Similarly, thecompounds of the invention may be utilised in the treatment ofconditions treatable by the inhibition of B-RAF and/or C-RAF.Furthermore, the compounds of the invention may be utilised in thetreatment of a condition which is modulated by B-RAF^(V600E). Inaddition the compounds of the invention may be utilised in the treatmentof conditions treatable by the inhibition of B-RAF^(V600E).B-RAF^(V600E) is a mutant form of wild type B-RAF which is believed toplay a role in aberrant MAPK pathway signalling, giving rise touncontrolled cell growth.

In an aspect of the invention there is provided a use of a compound ofthe invention for preventing cutaneous squamous cell carcinoma duringthe treatment of melanomas.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention are further described hereinafter withreference to the accompanying drawings, in which:

FIG. 1 is a graph showing reduced paradoxical activation of MAPK pathwayfor a compound of the invention (Example 3).

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “C₁₋₆ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl. Alkylene groups may likewise be linear or branched and may havetwo places of attachment to the remainder of the molecule. Furthermore,an alkylene group may, for example, correspond to one of those alkylgroups listed in this paragraph. The alkyl and alkylene groups may beunsubstituted or substituted by one or more substituents. Possiblesubstituents are described below. Substituents for the alkyl group maybe halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C₁₋₆alkoxy.

The term “C₁₋₆ alkoxy” refers to an alkyl group which is attached to amolecule via oxygen. This includes moieties where the alkyl part may belinear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, forexample methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may bemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy groupmay be unsubstituted or substituted by one or more substituents.Possible substituents are described below. Substituents for the alkylgroup may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH,C₁₋₆ alkoxy.

The term “C₁₋₆ haloalkyl” refers to a hydrocarbon chain substituted withat least one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the hydrocarbon chain. For example, C₁₋₆haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl,chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl.

The term “C₂₋₆ alkenyl” refers to a branched or linear hydrocarbon chaincontaining at least one double bond and having 2, 3, 4, 5 or 6 carbonatoms. The double bond(s) may be present as the E or Z isomer. Thedouble bond may be at any possible position of the hydrocarbon chain.For example, the “C₂₋₆ alkenyl” may be ethenyl, propenyl, butenyl,butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

The term “C₂₋₆ alkynyl” refers to a branched or linear hydrocarbon chaincontaining at least one triple bond and having 2, 3, 4, 5 or 6 carbonatoms. The triple bond may be at any possible position of thehydrocarbon chain. For example, the “C₂₋₆ alkynyl” may be ethynyl,propynyl, butynyl, pentynyl and hexynyl.

The term “C₁₋₆ heteroalkyl” refers to a branched or linear hydrocarbonchain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least oneheteroatom selected from N, O and S positioned between any carbon in thechain or at an end of the chain. For example, the hydrocarbon chain maycontain one or two heteroatoms. The C₁₋₆ heteroalkyl may be bonded tothe rest of the molecule through a carbon or a heteroatom. For example,the “C₁₋₆ heteroalkyl” may be C₁₋₆ N-alkyl, C₁₋₆ N,N-alkyl, or C₁₋₆O-alkyl.

The term “carbocyclic” refers to a saturated or unsaturated carboncontaining ring system. A “carbocyclic” system may be monocyclic or afused polycyclic ring system, for example, bicyclic or tricyclic. A“carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example,3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Carbocyclic” encompasses cycloalkyl moieties,cycloalkenyl moieties, aryl ring systems and fused ring systemsincluding an aromatic portion.

The term “heterocyclic” refers to a saturated or unsaturated ring systemcontaining at least one heteroatom selected from N, O or S. A“heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclicring system, for example, bicyclic or tricyclic. A “heterocyclic” moietymay contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atomsin a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.“Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenylmoieties and heteroaromatic moieties. For example, the heterocyclicgroup may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran,pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₈ cycloalkyl” refers to a saturated hydrocarbon ring systemcontaining 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the “C₃₋₈cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The term “C₃₋₈ cycloalkenyl” refers to an unsaturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.The ring may contain more than one double bond provided that the ringsystem is not aromatic. For example, the “C₃₋₈ cycloalkyl” may becyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene,cyclooctenyl and cycloatadienyl.

The term “C₃₋₈ heterocycloalkyl” refers to a saturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least oneheteroatom within the ring selected from N, O and S. For example theremay be 1, 2 or 3 heteroatoms, optionally 1 or 2. The “C₃₋₈heterocycloalkyl” may be bonded to the rest of the molecule through anycarbon atom or heteroatom. The “C₃₋₈ heterocycloalkyl” may have one ormore, e.g. one or two, bonds to the rest of the molecule: these bondsmay be through any of the atoms in the ring. For example, the “C₃₋₈heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane,tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine,oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine,morpholine, thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₈ heterocycloalkenyl” refers to an unsaturated hydrocarbonring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbonatoms and at least one heteroatom within the ring selected from N, O andS. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.The “C₃₋₈ heterocycloalkenyl” may be bonded to the rest of the moleculethrough any carbon atom or heteroatom. The “C₃₋₈ heterocycloalkenyl” mayhave one or more, e.g. one or two, bonds to the rest of the molecule:these bonds may be through any of the atoms in the ring. For example,the “C₃₋₈ heterocycloalkyl” may be tetrahydropyridine, dihydropyran,dihydrofuran, pyrroline.

The term “aromatic” when applied to a substituent as a whole means asingle ring or polycyclic ring system with 4n+2 electrons in aconjugated π system within the ring or ring system where all atomscontributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ringsystem has 4n+2 electrons in a conjugated π system within a ring whereall atoms contributing to the conjugated π system are in the same plane.For example, the “aryl” may be phenyl and naphthyl. The aryl systemitself may be substituted with other groups.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom within a single ring or within a fused ringsystem, selected from O, N and S. The ring or ring system has 4n+2electrons in a conjugated π system where all atoms contributing to theconjugated π system are in the same plane. For example, the “heteroaryl”may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole,pyrazole, pyrazine, pyridine, pyrimidine and indole.

The term “alkaryl” refers to an aryl group, as defined above, bonded toa C₁₋₄ alkyl, where the C₁₋₄ alkyl group provides attachment to theremainder of the molecule.

The term “alkheteroaryl” refers to a heteroaryl group, as defined above,bonded to a C₁₋₄ alkyl, where the alkyl group provides attachment to theremainder of the molecule.

The term “halogen” herein includes reference to F, Cl, Br and I. Halogenmay be Cl. Halogen may be F.

A bond terminating in a “

” represents that the bond is connected to another atom that is notshown in the structure. A bond terminating inside a cyclic structure andnot terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

Where a moiety is substituted, it may be substituted at any point on themoiety where chemically possible and consistent with atomic valencyrequirements. The moiety may be substituted by one or more substituents,e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituentson a group. Where there are two or more substituents, the substituentsmay be the same or different. The substituent(s) may be selected from:OH, NHR⁹, amidino, guanidino, hydroxyguanidino, formamidino,isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl or alkaryl. Where the group to be substituted is an alkylgroup the substituent may be ═O. Where the moiety is substituted withtwo or more substituents and two of the substituents are adjacent theadjacent substituents may form a C₄₋₈ ring along with the atoms of themoiety on which the substituents are substituted, wherein the C₄₋₈ ringis a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5,6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent. For example the groups below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

By “acyl” is meant an organic radical derived from, for example, anorganic acid by the removal of the hydroxyl group, e.g. a radical havingthe formula R—C(O)—, where R may be selected from H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C₁₋₃ alkyl.In one embodiment acyl is alkyl-carbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, acetyl, propionyl and butyryl.A particular acyl group is acetyl.

Throughout the description the disclosure of a compound also encompassespharmaceutically acceptable salts, solvates and stereoisomers thereof.Where a compound has a stereocentre, both (R) and (S) stereoisomers arecontemplated by the invention, equally mixtures of stereoisomers oraracemic mixture are completed by the present application. Where acompound of the invention has two or more stereocentres any combinationof (R) and (S) stereoisomers is contemplated. The combination of (R) and(S) stereoisomers may result in a diastereomeric mixture or a singlediastereoisomer. The compounds of the invention may be present as asingle stereoisomer or may be mixtures of stereoisomers, for exampleracemic mixtures and other enantiomeric mixtures, and diasteroemericmixtures. Where the mixture is a mixture of enantiomers the enantiomericexcess may be any of those disclosed above. Where the compound is asingle stereoisomer the compounds may still contain otherdiasteroisomers or enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. ofabout at least 85%

In embodiments where there is a single enantiomer of the compounds ofthe invention, the compounds of the invention may have an enantiomericpurity of at least about 90% enantiomeric excess (ee), at least about95% enantiomeric excess (ee), at least about 98% enantiomeric excess(ee), at least about 99% enantiomeric excess (ee), or 100% enantiomericexcess (ee). In embodiments where there is a mixture of enantiomers ofthe compounds of the invention, the compounds of the invention may be aracemic mixture or any other mixture of enantiomers, for example thecompounds of the invention may have an enantiomeric purity of at leastabout 50% enantiomeric excess (ee), at least about 60% enantiomericexcess (ee), at least about 70% enantiomeric excess (ee), at least about80% enantiomeric excess (ee), at least about 90% enantiomeric excess(ee), or at least about 95% enantiomeric excess (ee).

The invention contemplates pharmaceutically acceptable salts of thecompounds of formula (I). These may include the acid addition and basesalts of the compounds. These may be acid addition and base salts of thecompounds. In addition the invention contemplates solvates of thecompounds. These may be hydrates or other solvated forms of thecompound.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulfate and hemicalciumsalts. For a review on suitable salts, see “Handbook of PharmaceuticalSalts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid orbase;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of formula (I) or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of formula (I) to anotherby reaction with an appropriate acid or base or by means of a suitableion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of a number of formulaas herein defined, including all polymorphs and crystal habits thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of the invention.

Before purification, the compounds of the present invention may exist asa mixture of enantiomers depending on the synthetic procedure used. Theenantiomers can be separated by conventional techniques known in theart. Thus the invention covers individual enantiomers as well asmixtures thereof.

For some of the steps of the process of preparation of the compounds offormula (I), it may be necessary to protect potential reactive functionsthat are not wished to react, and to cleave said protecting groups inconsequence. In such a case, any compatible protecting radical can beused. In particular methods of protection and deprotection such as thosedescribed by T. W. GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protectinggroups, Georg Thieme Verlag, 1994), can be used. All of the abovereactions and the preparations of novel starting materials used in thepreceding methods are conventional and appropriate reagents and reactionconditions for their performance or preparation as well as proceduresfor isolating the desired products will be well-known to those skilledin the art with reference to literature precedents and the examples andpreparations hereto.

Also, the compounds of the present invention as well as intermediatesfor the preparation thereof can be purified according to variouswell-known methods, such as for example crystallization orchromatography.

The method of treatment or the compound for use in the treatment ofcancer, sarcoma, melanoma, skin cancer, haematologicaltumors, lymphoma,carcinoma and leukemia as defined hereinbefore may be applied as a soletherapy or be a combination therapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofcancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,carcinoma and leukemia may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof,such as alkylating agents (for example cis-platin, oxaliplatin,carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan,chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites(for example gemcitabine and antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed,cytosine arabinoside, and hydroxyurea); antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere and polokinase inhibitors); proteasome inhibitors, for examplecarfilzomib and bortezomib; interferon therapy; and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, mitoxantrone and camptothecin);(ii) cytostatic agents such as antiestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents, for example dasatinib and bosutinib(SKI-606), and metalloproteinase inhibitors, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies,for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab,tyrosine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family (for example EGFR family tyrosine kinase inhibitorssuch as gefitinib, erlotinib and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; modulators of protein regulators of cellapoptosis (for example Bcl-2 inhibitors); inhibitors of theplatelet-derived growth factor family such as imatinib and/or nilotinib(AMN107); inhibitors of serine/threonine kinases (for example Ras/RAFsignalling inhibitors such as farnesyl transferase inhibitors, forexample sorafenib, tipifarnib and lonafarnib), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitorsand cyclin dependent kinase inhibitors such as CDK2 and/or CDK4inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™);thalidomide; lenalidomide; and for example, a VEGF receptor tyrosinekinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib andpazopanib;(vi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;(vii) immunotherapy approaches, including for example antibody therapysuch as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) andofatumumab; interferons such as interferon α; interleukins such as IL-2(aldesleukin); interleukin inhibitors for example IRAK4 inhibitors;cancer vaccines including prophylactic and treatment vaccines such asHPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T(Provenge); toll-like receptor modulators for example TLR-7 or TLR-9agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1antagonists; and(viii) cytotoxic agents for example fludaribine (fludara), cladribine,pentostatin (Nipent™);(ix) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(x) targeted therapies, for example PI3Kd inhibitors, for exampleidelalisib and perifosine.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within a therapeutically effective dosage range describedhereinbefore and the other pharmaceutically-active agent within itsapproved dosage range.

According to a further aspect of the invention there is provided apharmaceutical product comprising a compound of formula (I), or apharmaceutically acceptable salt thereof as defined hereinbefore and anadditional active agent. The additional active agent may be ananti-tumour agent as defined hereinbefore for the combination treatmentof a condition modulated by a RAF kinase, for example B-RAF or C-RAF.

According to a further aspect of the invention there is provided amethod of treatment a condition modulated by a RAF kinase, for exampleB-RAF or C-RAF comprising administering a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesaltthereof simultaneously, sequentially or separately with anadditional anti-tumor agent, as defined hereinbefore, to a patient inneed thereof.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use simultaneously, sequentially or separately with an additionalanti-tumour agent as defined hereinbefore, in the treatment of acondition modulated by a RAF kinase, for example B-RAF or C-RAF.

According to another aspect of the invention there is provided a use ofthe compound of formula (I) in combination with an anti-tumor agent ashereinbefore described. The compound of formula (I) may be usedsimultaneously, sequentially or separately with the additionalanti-tumor agent The use may be in a single combination productcomprising the compound of formula (I) and the anti-tumor agent.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

The condition modulated by a RAF kinase, for example B-RAF or C-RAF,described above may be cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma and leukemia. Morespecifically the condition modulated by a RAF kinase, for example B-RAFor C-RAF, may be selected from: Barret's adenocarcinoma; biliary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors; primary CNS tumors; glioblastomas, astrocytomas;glioblastoma multiforme; ependymomas; seconday CNS tumors (metastases tothe central nervous system of tumors originating outside of the centralnervous system); brain tumors; brain metastases; colorectal cancer;large intestinal colon carcinoma; gastric cancer; carcinoma of the headand neck; squamous cell carcinoma of the head and neck; acutelymphoblastic leukemia; acute myelogenous leukemia (AML);myelodysplastic syndromes; chronic myelogenous leukemia; hairy cellleukaemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblasticleukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma;lung cancer; small cell lung cancer; non-small cell lung cancer; ovariancancer; endometrial cancer; pancreatic cancer; pituitary adenoma;prostate cancer; renal cancer; metastatic melanoma; and papilliarythyroid cancers. In particular, the condition modulated by a RAF kinase,for example B-RAF or C-RAF, may be selected from: melanoma, non-smallcell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breastcancer and cholangiocarcinoma.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (m/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semi-solid formulations of the compound of the invention maybe filled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquidpreparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient. The standard duration of treatment with compounds of theinvention is expected to vary between one and seven days for mostclinical indications. It may be necessary to extend the duration oftreatment beyond seven days in instances of recurrent infections orinfections associated with tissues or implanted materials to which thereis poor blood supply including bones/joints, respiratory tract,endocardium, and dental tissues.

Examples and Synthesis

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Reactionsheated in a microwave used a Biotage® Initiator Sixty. Compound identityand purity confirmations were performed by LCMS UV using a WatersAcquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detectorwavelength was 254 nM and the LCMS was in positive and negativeelectrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto aguard column (0.2 μm×2 mm filters) and UPLC column (C18, 50×2.1 mm, <2μm) in sequence maintained at 40° C. The samples were eluted at a flowrate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v)Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile)according to the gradients outlined in Table 1 below. Retention times RTare reported in minutes.

TABLE 1 Long Short Time (min) % A % B Time (min) % A % B 0 95 5 0 95 51.1 95 5 0.3 95 5 6.1 5 95 2 5 95 7 5 95 2.6 95 5 7.5 95 5 3 95 5 8 95 5

Chiral column conditions as follows:

TABLE 2 Instrument Agilent 1100 HPLC-DAD Column Chiralcel OZ-RH, 4.6 ×150 mm, 5 μM Analysis wavelength (nm) 254 nm Flow Rate (mL/min) 1.10mL/min Mobile Phase A 20 mM Ammonium bicarbonate (pH 9.0) Mobile Phase BAcetonitrile Standard diluent 1 mL Acetonitrile Sample diluent 1 mLMethanol Isocratic conditions Time (min) % A % B  0 40 60 20 40 60

NMR was also used to characterise final compounds. NMR spectra wereobtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe.

Compound purification was performed by flash column chromatography onsilica using a Biotage® Isolera One or by preparative LCMS. LCMSpurification was performed using a Waters 3100 Mass detector in positiveand negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Visdetector. Samples were eluted at a flow rate of 20 mL/min on a XBridge™prep C18 5 μM OBD 19×100 mm column with a mobile phase system composedof A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid inAcetonitrile) according to the gradient outlined in Table 2 below.

TABLE 3 Time (min) % A % B 0 70 30 1.5 70 30 11.7 5 95 13.7 5 95 14 7030 15 70 30

Chemical names were generated using mol2nam—Structure to Name Conversionby OpenEye Scientific Software. Starting materials were purchased fromcommercial sources or synthesised according to literature procedures.

Abbreviations: DCM—Dichloromethane; EtOAc—Ethyl acetate; MeOH—methanol;DMF—Dimethylacetamide; Hept—Heptane; pet. Ether—40/60 petroluem ether;Et₂O—Diethyl ether; tBuOH—tert butanol; hr(s)—hour or hours;sat—saturated; NaH—sodium hydride 60% in mineral oil; NaHCOs—sodiumhydrogen carbonate; Cs₂CO₃—Cesium carbonate; Brine—saturated aqueoussodium chloride solution; Na₂SO₄—anhydrous sodium sulphate;NH₄OAc—ammonium acetate; Sat aq NH₄Cl—saturated aqueous ammoniumchloride; AcOH—acetic acid; HCl—1N aqueous hydrochloric acid;TFA—trifluoroacetic acid; SCX-2—strong cationic resin;NEt₃-triethylamine; DIPEA—Diisopropylethylamine; MW—microwaveirradiation;HATU—1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; DMP—Dess-Martin Periodinane;CDCl₃—deuterated chloroform; MeOD₄—deuterated Methanol;d₆-DMSO—deuterated dimthylsulfoxide; Na—sodium; ^(t)Bu—tert butyl.

Preparation of intermediates useful in the synthesis of compounds of theinvention.

Intermediate 1: 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (PreparedAccording to J. Med. Chem. 2011, 54, 1836-1846.)

Intermediate 2: 6-hydroxychromane-3-carboxylic acid

Step 1.

To a solution of 2,5-dihydroxybenzaldehyde (5.33 g, 38.59 mmol) andpyridinium p-toluenesulfonate (0.97 g, 3.86 mmol) in DCM (165 mL) wasadded 3,4-dihydro-2H-pyran (3.8 mL, 41.68 mmol) dropwise. The reactionwas stirred for 18 hrs, diluted with DCM (150 mL), washed sat. aq.NaHCO₃ (250 mL)/brine (50 mL), dried (Na₂SO₄), filtered and concentratedin vacuo. The aqueous layer was extracted with EtOAc (400 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The combined organicresidues were purified by flash column chromatography (0-10% EtOAc/Hept)to provide 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (8.17 g, 95%yield) as a yellow solid.

LCMS (ES⁺, Short): RT 1.66 min, m/z 223.2 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ: 10.69 (1H, s), 9.84 (1H, d, J=0.5 Hz),7.28-7.24 (2H, m), 6.94-6.90 (1H, m), 5.34 (1H, t, J=3.3 Hz), 3.95-3.87(1H, m), 3.66-3.59 (1H, m), 2.04-1.93 (1H, m), 1.90-1.83 (2H, m),1.76-1.60 (3H, m).

Step 2:

To a solution of 2-hydroxy-5-tetrahydropyran-2-yloxybenzaldehyde (4.0 g,18 mmol) in DMF (60 mL) was added K₂CO₃ (2.49 g, 18 mmol) and tert-butylacrylate (3.95 mL, 27 mmol). The mixture was heated at 100° C. for 1 hr,then slowly raising the temperature from 100° C. to 135° C. (over 2 hrs)and maintained at 135° C. for 18 hrs. The reaction was cooled,concentrated in vacuo and the residue was partitioned between DCM (300mL) and water (250 mL). The aqueous layer was extracted with DCM (250mL), EtOAc (250 mL) and the combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (0-10% EtOAc/Hept) to provide tert-butyl6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (2.13 g, 36% yield)as a yellow solid.

LCMS (ES⁺, Short) RT 2.21 min. m/z 277.2 [M+H-^(t)Bu]⁺

¹H NMR (400 MHz, CDCl₃) δ: 7.31 (1H, br s), 6.94 (1H, dd, J=2.8, 8.6Hz), 6.89 (1H, d, J=2.8 Hz), 6.79 (1H, d, J=8.7 Hz), 5.31 (1H, t, J=3.2Hz), 4.93-4.89 (2H, m), 3.98-3.89 (1H, m), 3.66-3.58 (1H, m), 2.05-1.95(1H, m), 1.90-1.83 (2H, m), 1.73-1.60 (3H, m), 1.55 (9H, s).

Step 3

A solution of tert-butyl6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (2.15 g, 6.47 mmol)in MeOH (180 mL) was hydrogenated on the H Cube (10% Pd/C cartridge) for26 hrs. The solution was concentrated in vacuo to provide crudetert-butyl 6-tetrahydropyran-2-yloxychromane-3-carboxylate (2.01 g, 93%yield) as a pale yellow oil.

LCMS (ES⁺, Short) RT 2.10 min, m/z 357.3 [M+Na]⁺

Step 4:

To a solution of tert-butyl6-tetrahydropyran-2-yloxychromane-3-carboxylate (2.01 g, 6.01 mmol) inMeOH (30 mL) was added pyridinium p-toluenesulfonate (194 mg, 0.77 mmol)and the mixture was stirred for 18 hrs. The reaction was concentrated invacuo, partitioned between EtOAc (150 mL) and water (50 mL), washed withbrine (50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (0-30% EtOAc/Hept)to provide tert-butyl 6-hydroxychromane-3-carboxylate (1.48 g, 98%yield) as an off white solid.

LCMS (ES⁺, Short) RT 1.63 min, m/z 273.2 [M+Na]⁺

¹H NMR (400 MHz, CDCl₃) δ: 6.71 (1H, d, J=8.5 Hz), 6.63-6.57 (2H, m),4.52 (1H, s), 4.40-4.34 (1H, m), 4.07-4.00 (1H, m), 3.06-2.87 (3H, m),1.48 (9H, s).

Step 5:

To a solution of tert-butyl 6-hydroxychromane-3-carboxylate (1.48 g,5.91 mmol) in DCM (20 mL) was added TFA (10 mL, 130.68 mmol) and themixture stirred for 18 hrs. Further TFA (10 mL, 130.68 mmol) was addedand the reaction stirred for 72 hrs. The reaction was concentrated invacuo to provide 6-hydroxychromane-3-carboxylic acid (1.267 g, 110%yield) as an off white solid.

LCMS (ES⁻, Short) RT 1.03 min, m/z 193.1 [M−H]⁻

¹H NMR (400 MHz, CD₃OD) δ: 6.61-6.56 (1H, m), 6.53-6.49 (2H, m),4.33-4.25 (1H, m), 4.10-4.03 (1H, m), 2.99-2.88 (3H, m).

Intermediate 3:6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid

A mixture of 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (500. mg,3.01 mmol), 6-hydroxychromane-3-carboxylic acid (642.8 mg, 3.31 mmol)and Cs₂CO₃ (2.94 g, 9.03 mmol) in DMF (15 mL) was split into 2 MW vialsand irradiated at 150° C. for 1 hr. The combined reactions were dilutedwith water (100 mL), stirred for 10 mins, pH adjusted to −3 and theprecipitate was filtered and dried. The precipitate was purified bySCX-2 and flash column chromatography (1-10% MeOH/DCM) to provideintermediate 3[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid] (335 mg, 33% yield) as a light brown solid.

LCMS (ES⁺, Short) RT 1.25 min, m/z 341.3 [M+H]⁺

Intermediate 4: 6-hydroxy-2H-chromene-3-carboxylic acid

Step 1

Tert-butyl 6-hydroxy-2H-chromene-3-carboxylate was prepared using thematerial tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate(Intermediate 2, step 2) following the synthetic procedure fortert-butyl 6-hydroxychromane-3-carboxylate (Intermediate 2, step 4).

LCMS (ES⁻, Short) RT 1.73 min, m/z 247.2 [M−H]⁻

¹H NMR (400 MHz, DMSO) δ: 9.17 (1H, s), 7.34-7.31 (1H, m), 6.73-6.71(1H, m), 6.70-6.67 (2H, m), 4.67 (2H, d, J=1.4 Hz), 1.49 (9H, s).

Step 2

6-Hydroxy-2H-chromene-3-carboxylic acid was prepared using the materialtert-butyl 6-hydroxy-2H-chromene-3-carboxylate following the syntheticprocedure for 6-hydroxychromane-3-carboxylic acid (Intermediate 2, step5).

LCMS (ES⁻, Short) RT 1.13 min. m/z 191.2 [M−H]⁻

Intermediate 5:6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-carboxylicacid

6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-carboxylicacid (Intermediate 5) was prepared using the material5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (Intermediate 1) and6-hydroxy-2H-chromene-3-carboxylic acid (Intermediate 4) following thesynthetic procedure for6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (Intermediate 3)

LCMS (ES⁺, Short) RT 1.31 min, m/z 339.1 [M+H]⁺

¹H NMR (400 MHz, d₆-DMSO) δ: 12.90 (1H, br s), 10.49 (1H, s), 7.97 (1H,d, J=5.8 Hz), 7.47-7.43 (1H, m), 7.21 (1H, d, J=2.9 Hz), 7.09-7.05 (1H,m), 6.94 (1H, d, J=8.8 Hz), 6.29 (1H, d, J=5.8 Hz), 4.94 (2H, d, J=1.4Hz), 2.96-2.90 (2H, m), 2.57-2.51 (2H, m).

EXAMPLES Example 1:5-[3-(1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a mixture of o-phenylenediamine (20.27 mg, 0.19 mmol),6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (58 mg, 0.17 mmol) and DIPEA (0.12 mL,0.66 mmol) in DMF (2 mL) was added HATU (73.21 mg, 0.19 mmol). Themixture was stirred for 20 hrs, diluted with EtOAc (40 mL), washed brine(2×30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.

The residue was dissolved in AcOH (2 mL), heated at 80° C. for 4 hrs andconcentrated in vacuo. The residue was diluted with sat. aq. Na₂CO₃ (30mL), extracted with EtOAc (75, 50 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-6% MeOH/DCM) to provide5-[3-(1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(40 mg, 57% yield) as an off white solid.

LCMS: (ES⁺, Long): RT 2.11 min, m/z 413.3 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆ DMSO) δ: 12.61 (1H, br s), 10.47 (1H, s), 7.97 (1H,d, J=5.9 Hz), 7.57-7.50 (2H, m), 7.26-7.14 (2H, m), 7.03 (1H, d, J=2.6Hz), 6.94 (0.2H, d, J=2.7 Hz), 6.92 (0.8H, d, J=2.7 Hz), 6.90 (0.8H, s),6.88 (0.2H, s), 6.28 (1H, d, J=5.8 Hz), 4.64-4.56 (1H, m), 4.33-4.26(1H, m), 3.64-3.55 (1H, m), 3.27-3.18 (2H, m), 2.97-2.90 (2H, m),2.57-2.52 (2H, m).

Example 2: 5-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (50 mg, 0.15 mmol) and 3-chlorobenzene-1,2-diamine (22 mg, 0.15mmol) in DMF (2 mL) was added DIPEA (0.1 mL, 0.5700 mmol) and HATU(62.56 mg, 0.16 mmol). The mixture was stirred for 24 hrs, diluted withwater (15 mL) and extracted with EtOAc (60, 30 mL). The combined organiclayers were washed with brine (30 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo.

The residue was dissolved in AcOH (3 mL), heated at 80° C. for 20 hrs,cooled and concentrated in vacuo. The residuewas diluted with sat. aq.Na₂CO₃ (30 mL), extracted with EtOAc (75, 50 mL) and the combinedorganic layers were washed with brine (30 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography (0-5% and 2-5% MeOH/DCM) and prep HPLC to provide5-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(22.9 mg, 35% yield) as an off white solid.

LCMS (ES⁺, Long): RT 3.26 min, m/z 447.0, 449.0 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.82 (1H, br s), 10.47 (1H, s), 7.97 (1H,d, J=5.8 Hz), 7.54-7.44 (2H, m), 7.24 (1H, d, J=7.4 Hz), 7.17 (1H, t,J=7.8 Hz), 7.05 (1H, d, J=2.4 Hz), 6.95 (0.2H, d, J=2.6 Hz), 6.93 (0.8H,d, J=2.6 Hz), 6.92 (0.8H, s), 6.89 (0.2H, s), 6.28 (1H, d, J=5.8 Hz),4.65-4.57 (1H, m), 4.29 (0.5H, d, J=9.7 Hz), 4.27 (0.5H, 9.6 Hz),3.68-3.57 (1H, m), 3.27-3.12 (1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.53(2H, m).

Example 3:5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one]

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (97.48 mg, 0.71mmol) and 2-bromoacetophenone (93.59 mg, 0.47 mmol). The reaction wasstirred for 30 mins, diluted with water (30 mL) and extracted with EtOAc(2×50 mL). The combined organic layers were washed with brine (20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-5% MeOH/DCM) to provide ayellow solid (66 mg).

The residue as dissolved in AcOH (1 mL) and added to a solution ofNH₄OAc (181.22 mg, 2.35 mmol) in AcOH (1 mL). The mixture was heated at120° C. in a sealed vial for 72 hrs, cooled and concentrated in vacuo.The residue was diluted with sat. aq. NaHCO₃ (30 mL) and extracted withEtOAc (2×50 mL). The combined organic layers were washed with brine (30mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-5% and 2-5% MeOH/DCM) toprovide5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(20.2 mg, 20% yield) as an orange solid.

LCMS: (ES⁺, Long): RT 2.65 min, m/z 439.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.31 (0.2H, s), 12.09 (0.8H, s), 10.46(1H, s), 7.96 (1H, d, J=5.8 Hz), 7.77-7.73 (1.6H, m), 7.66-7.62 (0.4H,m), 7.60 (0.8H, d, J=2.0 Hz), 7.43-7.38 (0.5H, m), 7.36-7.30 (1.5H, m),7.28 (0.2H, d, J=1.6 Hz), 7.26-7.21 (0.3H, m), 7.19-7.13 (0.7H, m),7.03-6.99 (1H, m), 6.93 (0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.6 Hz),6.90 (0.8H, s), 6.88 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.55-4.48 (1H,m), 4.17-4.09 (1H, m), 3.45-3.35 (1H, m), 3.30-3.20 (1H, m), 3.17-3.07(1H, m), 2.97-2.90 (2H, m), 2.57-2.52 (2H, m).

Chiral purification of Example 3 provided two enantiomrs 3A and 3B:

Analytical Separation Method:

Instrument: Thar analytical SFC

Column: ChiraCel OJ-H, 250×4.6 mm

Mobile phase: A for CO₂ and B for MeOH (0.05% DEA)

Gradient: B 50%

Flow rate: 2.0 mL/min

Back pressure: 100 bar

Column temperature: 35° C.

Wavelength: 220 nm

Preparative Separation Method

Instrument: MG II preparative SFC

Column: ChiraCel OJ-H, 250×30 mml·D.

Mobile phase: A for CO₂ and B for MEOH

Gradient: B 50%

Flow rate: 50 mL/min

Back pressure: 100 bar

Column temperature: 38° C.

Wavelength: 220 nm

Cycletime: ˜7.0 min

Example 3A

Light tan solid (45.7 mg)

LCMS:(ES⁺, final purity): RT 2.67 min, m/z 439.2 [M+H]⁺

Chiral ee of enantiomer—99.5% [RT—7.26 mins]

Example 3B

Off white solid (48.1 mg)

LCMS: (ES⁺, final purity): RT 2.69 min, m/z 439.2 [M+H]⁺ Chiral ee ofenantiomer—99.7% [RT—8.46 mins]

Example 4:5-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80. mg, 0.24 mmol) and K₂CO₃ (0.04 mL, 0.47 mmol) in DMF (1 mL)was added a mixture of 4-(bromoacetyl)pyridine hydrobromide (0.07 mL,0.47 mmol) and NEt₃ (0.07 mL, 0.47 mmol) in DMF (1 mL). The mixture wasstirred for 30 mins, diluted with water (30 mL) and extracted with EtOAc(2×50 mL). The combined organic layers were washed with brine (30 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The combined aqueouslayers were extracted with EtOAc (100 mL) and the organic layer wasdried (Na₂SO₄), filtered and concentrated in vacuo.

The combined residues were dissolved in AcOH (2.5 mL), NH₄OAc (2.23 g,28.93 mmol) was added and the reaction heated in a sealed vial at 130°C. for 68 hrs. The reaction was cooled, concentrated in vacuo, added tosat. aq. NaHCO₃ (70 mL) and extracted with EtOAc (2×70 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by flash column chromatography (0-10% and 5-10%MeOH/DCM) to provide5-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(25 mg, 22% yield) as a yellow powder.

LCMS (ES⁺, Long): RT 2.40 min, m/z 440.1 [M+H]⁺.

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO δ 12.37 (1H, s), 10.47 (1H, s), 8.51-8.46 (2H,m), 7.96 (1H, d, J=5.8 Hz), 7.90 (1H, s), 7.71-7.67 (2H, m), 7.02 (1H,d, J=2.7 Hz), 6.94 (0.2H, d, J=2.7 Hz), 2.92 (0.8H, d, J=2.7 Hz), 6.90(0.8H, s), 6.88 (02H, s), 6.27 (1H, d, J=5.8 Hz), 4.54-4.49 (1H, m),4.15 (1H, t, J=10.2 Hz), 3.47-3.37 (1H, m), 3.27-3.20 (1H, m), 3.18-3.09(1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

Example 5: 5-[3-(4-tert-butyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.97 mg, 0.47mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.06 mL, 0.47 mmol). Thereaction was stirred for 30 mins, diluted with water (30 mL), extractedwith EtOAc (2×50 mL) and the combined organic layers were washed withbrine (30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo toprovide a brown solid (101 mg). The residue was dissolved in AcOH (3mL), NH₄OAc (2.23 g, 28.93 mmol) was added and the reaction heated in asealed tube at 130° C. for 120 hrs. The mixture was cooled, concentratedin vacuo. The residue was slowly added dropwise to sat. aq. NaHCO₃ (50mL) and extracted with EtOAc (2×100 mL). The combined organic layerswere washed with brine (30 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (0-5% MeOH/DCM) and SCX-2. The residue was dissolved inEtOAc (50 mL), washed with sat. aq. NaHCO₃ (50 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (0-5% MeOH/DCM) provided5-[3-(4-tert-butyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(10 mg, 10% yield) as an off white solid.

LCMS (ES⁺, Long): RT 2.57 min, m/z 419.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 11.62 (0.5H, s), 11.55 (0.5H, s), 10.46(1H, s), 7.96 (1H, dd, J=1.7, 5.8 Hz), 7.00-6.97 (1H, m), 6.92 (0.2H, d,J=2.8 Hz), 6.90 (0.8H, d, J=2.6 Hz), 6.89 (0.8H, s), 6.86 (0.2H, s),6.73 (0.5H, d, J=1.9 Hz), 6.46 (0.5H, d, J=1.8 Hz), 6.26 (1H, dd, J=0.9,5.8 Hz), 4.48-4.40 (1H, m), 4.07-3.97 (1H, td, J=3.8, 4.0 Hz), 3.32-3.24(1H, m), 3.20-3.10 (1H, m), 3.08-2.99 (1H, m), 2.93 (2H, t, J=7.7 Hz),2.57-2.53 (2H, m), 1.27 (5H, s), 1.19 (4H, s).

Example 6:5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.97 mg, 0.47mmol) and 3-(bromoacetyl)thiophene (0.07 mL, 0.47 mmol). The reactionwas stirred for 30 mins, diluted with water (30 mL) and extracted withEtOAc (2×50 mL). The combined organic layers were washed with brine (30mL), dried (Na₂SO₄), filtered and concentrated in vacuo to provide abrown solid (106 mg).

The solid was dissolved in AcOH (3 mL), NH₄OAc (2.23 g, 28.93 mmol) wasadded and the reaction heated in a sealed tube at 130° C. for 72 hrs.The mixture was cooled, concentrated in vacuo, the residue dissolved inEtOAc (50 mL) and washed with sat. aq. NaHCO₃ (2×50 mL) and water (50mL). The combined aqueous phases were extracted with EtOAc (50 mL) andthe combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (0-5% MeOH/DCM) and prep HPLC to provide5-[-3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(9.3 mg, 9% yield) as an off white solid.

LCMS (ES⁺, Long) RT 2.59 min, m/z 445.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆ DMSO) δ: 12.33 (0.3H, br s), 12.05 (0.7H, br s),10.47 (1H, s), 7.96 (1H, d, J=5.8 Hz), 7.60-7.38 (4H, m), 7.01 (1H, d,J=2.4 Hz), 6.93 (0.2H, d, J=2.5 Hz), 6.91 (0.8H, d, J=2.6 Hz), 6.90(0.8H, s), 6.89 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.53-4.63 (1H, m),4.11 (1H, t, J=10.3 Hz), 3.43-3.35 (1H, m), 3.28-3.18 (1H, m), 3.14-3.06(1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.53 (2H, m).

Example 7:5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.97 mg, 0.47mmol) and 2-bromo-1-(2-thienyl)ethanone (0.07 mL, 0.47 mmol). Thereaction was stirred for 30 mins, diluted with water (30 mL) andextracted with EtOAc (2×50 mL). The combined organic layers were washedwith brine (30 mL), dried (Na₂SO₄), filtered and concentrated in vacuoto provide a brown solid (159 mg). The solid was dissolved in AcOH (3mL), NH₄OAc (2.23 g, 28.93 mmol) was added and the reaction heated in asealed tube at 130° C. for 72 hours. The mixture was cooled,concentrated in vacuo and the residue dissolved in EtOAc (50 mL). Theorganic layer was washed with sat. aq. NaHCO₃ (2×50 mL) and water (50mL). The combined aqueous phases were extracted with EtOAc (50 mL) andthe combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (0-5% MeOH/DCM) and prep HPLC to provide5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(22.6 mg, 22% yield) as an off white solid.

LCMS (ES⁺, Long): RT 2.65 min, m/z 445.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.16 (1H, s), 10.46 (1H, s), 7.96 (1H, d,J=5.8 Hz), 7.46 (1H, s), 7.31 (1H, d, J=4.4 Hz), 7.22 (1H, d, J=3.0 Hz),7.02 (2H, m), 6.93 (0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.7 Hz), 6.90(0.8H, s), 6.87 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.52-4.44 (1H, m),4.11 (1H, t, J=10.3 Hz), 3.43-3.35 (1H, m), 3.26-3.17 (1H, m), 3.14-3.06(1H, m), 2.93 (2H, t, J=7.7 Hz), 2.57-2.53 (2H, m).

Example 8:5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (70 mg, 0.21 mmol) in DMF (2 mL) was added K₂CO₃ (56.86 mg, 0.41mmol) and 2-bromo-1-(2-chlorophenyl)ethanone (59.9 uL, 0.41 mmol). Thereaction was stirred for 2 hrs, diluted with water (20 mL) and extractedwith EtOAc (50 mL). The organic layer was washed with water (30 mL),brine (20 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (0-5% MeOH/DCM) toprovide a solid.

The solid was dissolved in AcOH (3 mL) and NH₄OAc (1.58 g, 20.57 mmol)was added. The mixture was heated in a seal vial at 140° C. for 24 hrs,cooled and added to sat. aq. NaHCO₃ (250 mL)/EtOAc (50 mL). The mixturewas stirred for 1 hr, diluted with EtOAc (100 mL) and the combinedorganic layers were washed with brine (100 mL). The combined aqueouslayers were extracted with EtOAc (100 mL) and the combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (0-5% MeOH/DCM) andprep HPLC to provide5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(14.1 mg, 14% yield) as an off white solid.

LCMS: (ES⁺, Long): RT 2.88 min, m/z 473.1, 475.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.34 (0.2H, s), 12.28 (0.8H, s), 10.46(1H, s), 8.13-8.08 (1H, m), 7.95 (1H, d, J=6.0 Hz), 7.74 (1H, s),7.47-7.42 (1H, m), 7.38-7.32 (1H, m), 7.24-7.18 (1H, m), 7.02-6.99 (1H,m), 6.93 (0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.6 Hz), 6.90 (0.8H, s),6.87 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.55-4.49 (1H, m), 4.15 (1H, t,J=10.2 Hz), 3.48-3.37 (1H, m), 3.29-3.21 (1H, m), 3.18-3.08 (1H, m),2.93 (2H, t, J=7.7 Hz), 2.56-2.52 (2H, m).

Example 9:5-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (70 mg, 0.21 mmol) in DMF (2 mL) was added K₂CO₃ (56.86 mg, 0.41mmol) and 2-bromo-1-(3-chlorophenyl)ethanone (96.06 mg, 0.41 mmol). Thereaction was stirred for 3 days and further2-bromo-1-(3-chlorophenyl)ethanone (96.06 mg, 0.41 mmol) and K₂CO₃(56.86 mg, 0.41 mmol) were added. The mixture was stirred for 24 hrs,diluted with water (50 mL) and extracted with EtOAc (2×50 mL). Theorganic layers were washed with brine (50 mL). The combined aqueouslayers were extracted with EtOAc (50 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo to provide asolid.

The solid was dissolved in AcOH (3 mL) and NH₄OAc (1.59 g, 20.57 mmol)was added. The mixture was heated in a sealed vial at 140° C. for 24hrs. The mixture was added to sat. aq. NaHCO₃ (250 mL) and extractedwith EtOAc (200 mL). The organic layer was washed with brine (2×100 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-5% MeOH/DCM) to provide5-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(10.1 mg, 10% yield) as a brown solid.

LCMS (ES⁺, Long): RT 3.04 min, m/z 473.1, 475.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.40 (0.2H, s), 12.31 (0.8H, s), 10.46(1H, s), 7.96 (1H, d, J=5.8 Hz), 7.80 (0.8H, t, J=1.8 Hz), 7.76-7.69(2.2H, m), 7.36 (1H, t, J=7.9 Hz), 7.23-7.19 (1H, m), 7.03-7.00 (1H, m),6.94 (0.2H, d, J=2.6 Hz) 6.91 (0.8H, d, J=2.6 Hz), 6.89 (0.7H, s), 6.88(0.3H, s), 6.27 (1H, d, J=5.8 Hz), 4.54-4.48 (1H, m), 4.14 (1H, t,J=10.2 Hz), 3.44-3.36 (1H, m), 3.29-3.20 (1H, m), 3.16-3.08 (1H, m),2.93 (2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

Example 10:5-[3-[4-(benzofuran-3-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (70 mg, 0.21 mmol) and K₂CO₃ (56.85 mg, 0.41 mmol) in DMF (2 mL)was added 1-(benzofuran-3-yl)-2-bromo-ethanone (98.35 mg, 0.41 mmol).The reaction was stirred for 1.5 hrs, diluted with water (10 mL) andextracted with EtOAc (80 mL). The organic layer was washed with water(30 mL), brine (30 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by flash column chromatography (0-5%MeOH/DCM) to provide a beige solid (104 mg).

The solid was dissolved in AcOH (4 mL), NH₄OAc (1.49 g, 19.27 mmol) wasadded and the mixture heated at 140° C. in a sealed vial for 18 hrs. Thereaction was cooled, added to water (40 mL), pH adjusted to 8-9 andextracted with EtOAc (2×150 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography (0-10% MeOH/DCM) and prep HPLC to provide5-[3-[4-(benzofuran-3-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(6 mg, 6% yield) as an off white solid.

LCMS (ES⁺, Long): RT 2.98 min, m/z 479.2 [M+H]⁺

1H NMR shows a mixture of confirmers:

1H NMR (400 MHz, d₆DMSO) δ: 12.42 (0.2H, br s), 12.21 (0.8H, brs), 10.47(1H, s), 8.25 (0.2H, br s), 8.18 (0.8H, s), 8.11-8.04 (1H, m), 7.96 (1H,d, J=5.8 Hz), 7.58-7.56 (2H, m), 7.44-7.28 (2H, m), 7.03 (1H, d, J=2.4Hz), 6.94 (0.2H, d, J=2.9 Hz), 6.92 (0.8H, d, J=2.6 Hz), 6.91 (0.8H, s),6.89 (0.2H, s), 6.28 (1H, d, J=5.8 Hz), 4.57-4.50 (1H, m), 4.16 (1H, t,J=10.3 Hz), 3.48-3.39 (1H, m), 3.30-3.23 (1H, m), 3.19-3.10 (1H, m),2.94 (2H, t, J=7.7 Hz), 2.58-2.52 (2H, m).

Example 11:5-[3-[5-(3-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.99 mg, 0.47mmol) and 2-bromo-1-(3-pyridyl)ethanone hydrobromide (132.1 mg, 0.47mmol). The reaction was 1 hr, diluted with water (20 mL) and extractedwith EtOAc (50 mL). The organic layer was washed with water (30 mL) andbrine (50 mL). The combined aqueous layers were extracted with EtOAc (50mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified using flash columnchromatography (0-5% MeOH/DCM) to provide a dark brown oil (100 mg). Thebrown oil was dissolved in AcOH (3 mL), NH₄OAc (1.82 g, 23.51 mmol) wasadded and the mixture heated in a sealed vial at 140° C. for 18 hrs. Themixture was added to sat. aq. NaHCO₃ (250 mL) and EtOAc (50 mL) andstirred for 1 hr. The mixture was diluted with EtOAc (100 mL). Theorganic layer was washed with brine (100 mL) and the combined aqueouslayers were extracted with EtOAc (100 mL). The combined organic layerswere dried (Na₂SO₄), filtered, concentrated in vacuo and the residue waspurified by prep HPLC to provide5-[3-[5-(3-pyridyl)-1H-imidazol-2-yl]chroman-6-_(yl]oxy-)3,4-dihydro-1H-1,8-naphthyridin-2-one(7 mg, 7% yield) as an off white solid.

LCMS (ES⁺, Long): RT 2.40 min, m/z 440.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.26 (1H, s), 10.46 (1H, s), 8.97 (1H, s),8.40-8.35 (1H, m), 8.10-8.04 (1H, m), 7.96 (1H, d, J=5.8 Hz), 7.75 (1H,s), 7.38-7.33 (1H, m), 7.04-7.00 (1H, m), 6.94 (0.2H, d, J=2.6 Hz), 6.92(0.8H, d, J=2.6 Hz), 6.90 (0.8H, s), 6.88 (0.2H, s), 6.27 (1H, d, J=5.8Hz), 4.55-4.48 (1H, m), 4.15 (1H, t, J=10.3 Hz), 3.47-3.38 (1H, m),3.29-3.21 (1H, m), 3.18-3.10 (1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.52(2H, m).

Example 12:5-[3-[5-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthridin-2-one

To a stirred mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.99 mg, 0.47mmol) and 4-Methylsulfonyl alpha-bromoacetophenone (130.31 mg, 0.47mmol). The reaction was stirred for 1 hr, diluted with water (20 mL) andextracted with EtOAc (50 mL). The organic layer was washed with water(30 mL) and brine (50 mL). The combined aqueous layers were extractedwith EtOAc (50 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo to provide a dark orange solid (100mg).

The orange solid was dissolved in AcOH (3 mL), NH₄OAc (1.81 g, 23.51mmol) was added and the mixture heated in a sealed vial at 140° C. for18 hrs. The mixture was added to sat. aq. NaHCO₃ (250 mL) and EtOAc (50mL) and stirred until neutralised. Further EtOAc (100 mL) was added andthe organic layer was washed with brine (100 mL). The combined aqueouslayers were extracted with EtOAc (100 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified using flash column chromatography (0-5% MeOH/DCM and 0-5%MeOH/DCM) and prep HPLC to provide5-[3-[5-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(26.8 mg, 22% yield) as a pale yellow solid.

LCMS (ES⁺, Long): RT 2.62 min, m/z 517.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.35 (1H, s), 10.46 (1H, s), 8.02-7.95(3H, m), 7.90-7.84 (3H, m), 7.04-7.00 (1H, m), 6.95-6.87 (2H, m), 6.27(1H, d, J=5.8 Hz), 4.56-4.49 (1H, m), 4.15 (1H, t, J=10.2 Hz), 3.48-3.38(1H, m), 3.28-3.21 (1H, m), 3.20 (3H, s), 3.18-3.09 (1H, m), 2.94 (2H,t, J=7.7 Hz), 2.57-2.52 (2H, m).

Example 13:5-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (80 mg, 0.24 mmol) in DMF (2 mL) was added K₂CO₃ (64.99 mg, 0.47mmol) and p-fluorophenacyl bromide (102.05 mg, 0.47 mmol). The reactionwas stirred for 1 hr, diluted with water (20 mL) and extracted withEtOAc (50 ml). The organic layer was washed with water (30 mL) and brine(50 mL). The combined aqueous layers were extracted with EtOAc (50 mL).The combined organic layers were combined dried (Na₂SO₄), filtered,concentrated in vacuo and purified by flash column chromatography (0-5%MeOH/DCM) to provide a dark brown oil.

The brown oil was dissolved in AcOH (3 mL), NH₄OAc (1.81 g, 23.51 mmol)was added and the mixture heated in a sealed vial at 140° C. for 18 hrs.The mixture was added to sat. aq. NaHCO₃ (100 mL) and EtOAc (50 mL) andstirred until neutralised. The mixture was diluted with EtOAc (50 mL)and the combined organic layers were washed with brine (50 mL). Thecombined aqueous layers were extracted with EtOAc (50 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by flash column chromatography (0-5% MeOH/DCM)and prep HPLC to provide5-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(7.7 mg, 7% yield) as an off white solid.

LCMS: (ES⁺, Long): RT 2.76 min, m/z 457.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.33 (0.2H, s), 12.11 (0.8H, s), 10.46(1H, s), 7.96 (1H, d, J=5.8 Hz), 7.81-7.74 (1.7H, m), 7.70-7.64 (0.3H,m), 7.58 (0.8H, s), 7.29-7.23 (0.5H, m), 7.20-7.12 (1.7H, m), 7.03-6.99(1H, m), 6.94 (0.2H, d, J=2.6 Hz), 6.91 (0.8H, d, J=2.6 Hz), 6.90 (0.8H,s), 6.88 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.54-4.48 (1H, m), 4.13 (1H,t, J=10.3 Hz), 3.45-3.36 (1H, m), 3.29-3.19 (1H, m), 3.16-3.07 (1H, m),2.94 (2H, t, J=7.7 Hz), 2.57-2.53 (2H, m).

Example 14:5-[3-[5-(1,3-benzodioxol-5-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (160 mg, 0.47 mmol) in DMF (4 mL) was added K₂CO₃ (129.95 mg, 0.94mmol) and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (228.53 mg, 0.94mmol). The reaction was stirred for 2 hrs, diluted with water (20 mL)and extracted with EtOAc (50 mL). The organic layer was washed withwater (30 mL) and brine (50 mL). The combined aqueous layers wereextracted with EtOAc (50 mL). The combined organic layers were dried(Na₂SO₄), filtered, concentrated in vacuo and residue was purified byflash column chromatography (0-5% MeOH/DCM) to provide a yellow oil.

The yellow oil was dissolved in AcOH (6 mL), NH₄OAc (3.62 g, 47.01 mmol)was added and the mixture heated in a sealed tube at 140° C. for 3 hrs.The mixture was diluted with sat. aq. NaHCO₃ (250 mL) and EtOAc (50 mL)and stirred till neutralised. The biphasic mixture was diluted withEtOAc (100 mL). The organic layer was washed with brine (100 mL) and thecombined aqueous layers were extracted with EtOAc (100 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated invacuo.The residue was purified using flash column chromatography (0-5%DCM/MeOH) and HPLC prep to provide5-[3-[5-(1,3-benzodioxol-5-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(13.8 mg, 6% yield) as an off white solid.

LCMS (ES⁺, Long): RT 2.71 min, m/z 483.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.19 (0.2H, s), 12.02 (0.8H, s), 10.45(1H, s), 7.95 (1H, d, J=5.9 Hz), 7.50-7.45 (1H, m), 7.30-7.10 (2H, m),7.01-6.98 (1H, m), 6.94-6.84 (3H, m), 6.26 (1H, d, J=5.7 Hz), 6.05-5.96(2H, m), 4.52-4.46 (1H, m), 4.11 (1H, t, J=10.2 Hz), 3.41-3.34 (1H, m),3.27-3.18 (1H, m), 3.13-3.05 (1H, m), 2.93 (2H, t, J=7.7 Hz), 2.57-2.52(2H, m).

Example 15:5-[3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (160 mg, 0.47 mmol) in DMF (4 mL) was added K₂CO₃ (129.95 mg, 0.94mmol) and 3,4-(Ethylenedioxy)phenacyl bromide (168 mg, 0.65 mmol). Thereaction was stirred for 1 hr, diluted with water (20 mL) and extractedwith EtOAc (50 mL). The organic layer was washed with water (30 mL) andbrine (50 mL). The combined aqueous layers were extracted with EtOAc (50mL). The combined organic layers were dried (Na₂SO₄), filtered,concentrated invacuo and residue purified by flash column chromatography(0-5% MeOH/DCM) to provide a yellow oil.

The yellow oil was dissolved in AcOH (6 mL), NH₄OAc (3.62 g, 47.01 mmol)was added and the mixture heated in a sealed tube at 140° C. for 1.5hrs, cooled and stirred for a further 90 hrs. The mixture was dilutedwith sat. aq. NaHCO₃ (150 mL), EtOAc (50 mL) and stirred tillneutralised. The mixture was diluted with further EtOAc (50 ml). Theorganic layer was washed with brine (100 mL) and the combined aqueouslayers were extracted with EtOAc (100 mL). The combined organic layerswere dried (Na₂SO₄), filtered, concentrated in vacuo. The residue waspurified by flash column chromatography (0-5% DCM/MeOH) and prep HPLC toprovide5-[3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(21.6 mg, 9% yield) as an off white solid

LCMS: (ES⁺, Long): RT 2.73 min, m/z 497.1 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.02 (1H, s), 10.47 (1H, s), 7.96 (1H, d,J=5.8 Hz), 7.42 (1H, s), 7.24-7.15 (2H, m), 7.02-6.98 (1H, m), 6.93(0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.7 Hz), 6.89 (0.8H, s), 6.88(0.2H, s), 6.82 (1H, d, J=8.5 Hz), 6.27 (1H, d, J=5.8 Hz), 4.53-4.46(1H, m), 4.24 (4H, s), 4.12 (1H, t, J=10.3 Hz), 3.42-3.34 (1H, m),3.27-3.18 (1H, m), 3.15-3.06 (1H, m), 2.93 (2H, t, J=7.7 Hz), 2.57-2.52(2H, m).

Example 16:5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H-chromen-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a solution of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-carboxylicacid (354 mg, 1.05 mmol) in DMF (7 mL) was added K₂CO₃ (289.13 mg, 2.09mmol) and 2-bromoacetophenone (0.31 mL, 2.09 mmol). The reaction wasstirred for 30 mins at room temperature, diluted with water (30 mL) andextracted with EtOAc (2×50 mL). The combined organic layers were washedwith brine (30 mL), dried (Na₂SO₄), filtered and 60 concentrated invacuo to provide a brown solid.

The solid was dissolved in AcOH (10 mL), NH₄OAc (6.45 g, 83.71 mmol) wasadded and the reaction heated in a sealed tube at 130° C. for 16 hrs.The mixture was cooled, concentrated in vacuo and the residue dissolvedin EtOAc (50 mL). The organic layer was washed with sat. aq. NaHCO₃(2×50 mL) and water (1×50 mL). The combined aqueous layers wereextracted with EtOAc (50 mL) and the combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography (0-5% MeOH/DCM) and prep HPLC to provide5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H-chromen-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one(21 mg, 5% yield) as a yellow solid.

LCMS (ES⁺, Long) RT 3.14 min, m/z 437.2 [M+H]⁺

¹HNMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.73 (0.8H, br s), 12.70 (0.2H, br s),10.48 (1H, s), 7.98 (1H, d, J=5.8 Hz), 7.86-7.75 (2H, m), 7.53-7.28 (3H,m), 7.25-7.18 (1H, m), 7.15 (1H, br s), 7.02 (1H, t, J=1.5 Hz), 6.95(2H, d, J=1.6 Hz), 6.33 (1H, d, J=5.8 Hz), 5.27 (1.5H, s), 5.23 (0.5H,s), 2.98-2.91 (2H, m), 2.58-2.52 (2H, m).

Example 17: 5-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

To a mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (62 mg, 0.18 mmol), N-Hydroxybenzenecarboximidamide (26 mg, 0.19mmol) and DIPEA (0.05 mL, 0.27 mmol) in DMF (2 mL) was added HATU (79.66mg, 0.21 mmol). The reaction was stirred for 22 hrs, quenched with water(15 mL) and extracted with EtOAc (50 mL). The aqueous layer was dilutedwith EtOAc (50 mL), filtered, diluted with further EtOAc (150 mL) andbrine (50 mL), separated and the combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo.

The residue was dissolved in pyridine (3 mL, 37.09 mmol) and heated at100° C. in a sealed vial for 20 hrs. The mixture was cooled,concentrated in vacuo and the residue was purified by flash columnchromatography (0-5% MeOH/DCM) and prep HPLC to provide5-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(5 mg, 6% yield) as an off white solid.

LCMS (ES⁺, Long): RT 4.11 min, m/z 441.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 10.47 (1H, s), 8.03-7.97 (2H, m), 7.96 (1H,d, J=5.8 Hz), 7.64-7.54 (3H, m), 7.07 (1H, d, J=2.5 Hz), 6.95 (0.3H, d,J=2.7 Hz), 6.93 (0.7H, d, J=2.7 Hz), 6.91 (0.7H, s), 6.89 (0.3H, s),6.26 (1H, d, J=5.8 Hz), 4.63-4.56 (1H, m), 4.48-4.40 (1H, dd, J=7.4 Hz),3.98-3.88 (1H, m), 3.40-3.25 (2H, m), 2.93 (2H, t, J=7.4, 10.9 Hz),2.57-2.53 (2H, m).

Example 18: 5-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one

Step 1:

To a mixture of6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylicacid (150 mg, 0.44 mmol) and N,O-Dimethylhydroxylamine hydrochloride(64.49 mg, 0.66 mmol) in DMF (3 mL) was added DIPEA (0.31 mL, 1.76 mmol)and HATU (201.1 mg, 0.53 mmol). The mixture was stirred for 24 hrs,diluted with EtOAc (100 mL), washed with water (233 30 mL), brine (30mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-4% MeOH/DCM) to provideN-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxamide(133 mg, 79% yield) as an off white foam.

LC-MS (ES⁺, Short): RT 1.37 min, m/z 384.2 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (1H, s), 7.96 (1H, d, J=6.0 Hz),6.90-6.86 (1H, m), 6.85-6.80 (2H, m), 6.31 (1H, d, J=5.9 Hz), 4.46-4.40(1H, m), 4.04 (1H, t, J=10.5 Hz), 3.76 (3H, s), 3.42-3.32 (1H, m), 3.24(3H, s), 3.20-3.11 (1H, m), 3.06 (2H, t, J=7.5 Hz), 2.90-2.83 (1H, m),2.73-2.66 (2H, m).

Step 2:

To a solution of phenylacetylene (0.09 mL, 0.85 mmol) in THF (6 mL) at−78° C. was added dropwise n-Butyllithium solution (0.34 mL, 0.85 mmol,2.5M in THF) and the solution stirred for 30 mins. A solution ofN-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxamide (130 mg, 0.34 mmol) in THF (2 mL) was addeddropwise and the solution stirred for 3 hrs at −78° C. then warmed toroom temperature over 1 hr. The reaction was quenched with sat. aq.NH₄Cl (20 mL) and extracted with EtOAc (100 mL). The organic layer waswashed with brine (20 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by flash column chromatography (0-5%MeOH/DCM) to provide5-[3-(3-phenylprop-2-ynoyl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(122 mg, 61% yield) as a yellow solid.

LCMS (ES⁺, Short): RT 1.76 min, m/z 425.3 [M+H]^(+.)

Step 3:

To a solution of5-[3-(3-phenylprop-2-ynoyl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(122 mg, 0.21 mmol) in ^(t)BuOH (2 mL) was added hydrazine hydrate (0.02mL, 0.41 mmol) and the mixture heated to 85° C. for 18 hrs. The mixturewas cooled, concentrated in vacuo and purified by flash columnchromatography (0-5% MeOH/DCM) and prep HPLC to provide5-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one(20 mg, 22% yield) as an off white solid.

LCMS (ES⁺, Long): RT 3.71 min, m/z 439.2 [M+H]⁺

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 13.14 (0.5H, br s), 12.88 (0.5H, br s),10.47 (1H, s), 7.96 (1H, d, J=5.8 Hz), 7.82-7.65 (2H, m), 7.50-7.24 (3H,m), 6.99 (1H, d, J=2.4 Hz), 6.96-6.85 (2H, m), 6.70-6.57 (1H, m), 6.27(1H, d, J=5.8 Hz), 4.50-4.40 (1H, m), 4.19-4.02 (1H, m), 3.40-3.30 (1H,m), 3.17-3.03 (2H, m), 2.93 (2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

Example 19: 5-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one

Step 1:

To a suspension of NaH (60%, 0.82 g, 20.58 mmol) in DMF (20 mL) at 0° C.was added slowly a solution of2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (3.43 g, 15.43 mmol) inDMF (20 mL) and the mixture stirred for 1 hr. [(2R)-oxiran-2-yl]methyl3-nitrobenzenesulfonate (4.g, 15.43 mmol) was added, the mixture warmedto room temperature and heated at 70° C. for 18 hrs. The reaction wascooled and concentrated in vacuo. The residue was dissolved in DCM (200mL), washed with aq. 1 M HCl (100 mL), sat. aq. Na₂CO₃ (100 mL) andbrine (50 mL). The aqueous layers were extracted with DCM (2×200 mL) andthe combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (0-50% EtOAc/pet. Ether) to provide2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-benzaldehyde(2.06 g, 48% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ: 10.47 (1H, s), 7.51 (1H, d, J=3.1 Hz),7.26-7.21 (1H, m), 6.93 (1H, d, J=8.8 Hz), 5.35 (1H, t, J=3.3 Hz), 4.34(1H, dd, J=2.9, 11.2 Hz), 4.02 (1H, dd, J=5.7, 11.1 Hz), 3.93-3.83 (1H,m), 3.63-3.56 (1H, m), 3.41-3.35 (1H, m), 2.93 (1H, t, J=4.5 Hz),2.79-2.75 (1H, m), 2.03-1.91 (1H, m), 1.88-1.79 (2H, m), 1.74-1.50 (3H,m).

Step 2:

To a solution of2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-benzaldehyde(2.06 g, 7.39 mmol) in DCM (25 mL) was added mCPBA (2.55 g, 14.79 mmol).The mixture was stirred for 18 hrs, filtered and concentrated in vacuo.The residue was dissolved in Et₂O, washed with aq. sodium thiosulphate,sat. aq. Na₂CO₃, brine, dried (Na₂SO₄), filtered and concentrated invacuo to provide crude[2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-phenyl]formate(2.08 g, 95% yield).

¹H NMR (400 MHz, CDCl₃) δ: 8.26 (1H, s), 6.97-6.89 (2H, m), 6.87 (1H, d,J=2.6 Hz), 5.30 (1H, t, J=3.2 Hz), 4.19 (1H, dd, J=3.3, 11.4 Hz), 3.96(1H, dd, J=5.6, 11.2 Hz), 3.92-3.83 (1H, m), 3.63-3.55 (1H, m),3.32-3.26 (1H, m), 2.89-2.85 (1H, m), 2.70 (1H, dd, J=2.7, 4.9 Hz),2.02-1.78 (3H, m), 1.73-1.58 (3H, m).

Step 3:

To a solution of[2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-phenyl] formate(2.08 g, 7.07 mmol) in MeOH (42.3 mL) was added Na₂CO₃ (2.1 g, 19.79mmol) and the mixture stirred for 70 hrs. The mixture was diluted withDCM and washed with water. The aqueous layer was extracted with DCM andthe combined organic layers were dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (0-50% EtOAc/pet. Ether) to provide[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]methanol(1.76 g, 94% yield) as a clear, pale yellow oil.

LC/MS: (ES⁺, Short): RT 1.51 min, m/z 267.0 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ: 6.78 (1H, d, J=8.9 Hz), 6.67 (1H, d, J=3.0Hz), 6.59-6.53 (1H, m), 5.29-5.24 (1H, m), 4.28-4.21 (2H, m), 4.06 (1H,dd, J=8.2, 11.9 Hz), 3.96-3.79 (2H, m), 3.63-3.55 (1H, m), 2.03-1.78(4H, m), 1.72-1.52 (4H, m).

Step 4

[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]methanol(500 mg, 1.88 mmol) was dissolved in DCM (8 mL) and cooled to 0° C. DMP(0.88 g, 2.07 mmol) was added and the reaction was stirred for 3 hrs.The mixture was diluted with sat. aq. NaHCO₃ (10 mL)/sat. aq. sodiumthiosulphate (10 mL) and stirred for 1 hr. The layers were separated andthe aqueous layer was extracted with DCM (15 mL), The combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo toprovide crude(3R)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxine-3-carbaldehyde(586 mg, 118% yield) as an orange oil.

Step 5:

A solution of phenylglyoxal hydrate (285.57 mg, 1.88 mmol) in MeOH (10mL) was added dropwise to a stirred suspension of crude(3R)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxine-3-carbaldehyde(496 mg, 1.88 mmol) and NH₄OAc (704.54 mg, 9.14 mmol) in MeOH (8 mL).The reaction mixture was stirred for 18 hrs and concentrated in vacuo.The residue was partitioned between sat. aq. NaHCO₃ (20 mL) and DCM (20mL). The organic phase was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by column chromatography (0-30%EtOAc/pet. Ether) to provide4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]-1H-imidazole(550 mg, 77%).

LC/MS (ES⁺, Short): RT 1.57 min, m/z 379.2 [M+H]⁺

Step 6:

To a solution of4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]-1H-imidazole(550 mg, 1.45 mmol) in DMF (9.4 mL), at 0° C., was added NaH (60%, 75.57mg, 1.89 mmol) and the mixture stirred at this temperature for 1 hr.2-(Trimethylsilyl)ethoxymethyl chloride (257.23 uL, 1.45 mmol) was addeddropwise at 0° C. and the mixture stirred for 16 hrs at roomtemperature. The mixture was quenched with sat. aq. NH₄Cl (5 mL) andextracted with EtOAc (25 mL). The organic layer was washed with water(25 mL) and the combined aqueous layers were extracted with EtOAc (25mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo to provide crudetrimethyl-[2-[[4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]imidazol-1-yl]methoxy]ethyl]silane(1.30 g, 176% yield) as a pale yellow oil.

LC/MS: (ES⁺, Short): RT 2.36 min, m/z 509.6 [M+H]⁺

Step 7:

Trimethyl-[2-[[4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]imidazol-1-yl]methoxy]ethyl]silane(739 mg, 1.45 mmol) was dissolved in MeOH (5 mL), loaded onto apre-wetted 5 g SCX cartridge and washed with methanol (3×15 mL), 1 NNH₃/MeOH (3×15 mL), and product fractions were concentrated in vacuo.The residue was purified by column chromatography (0-25% EtOAc/pet.Ether) to provide(3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-ol(260 mg, 42% yield) as a pale yellow oil.

LC/MS: (ES⁺, Short): RT 2.02 min, m/z 425.4 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ: 7.78-7.73 (2H, m), 7.40-7.35 (2H, m), 7.33(1H, s), 7.29-7.27 (0.5H, m), 7.25-7.23 (0.5H, m), 6.77 (1H, d, J=8.8Hz), 6.52 (1H, d, J=3.0 Hz), 6.40-6.29 (2H, m), 5.52 (1H, d, J=10.8 Hz),5.39-5.32 (2H, m), 4.61-4.51 (2H, m), 3.59 (2H, t, J=8.3 Hz), 0.97-0.87(2H, m), 0.00-0.02 (9H, s).

Step 8:

(3S)-3-[4 -phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-ol(115 mg, 0.27 mmol), 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (45mg, 0.27 mmol) and Cs₂CO₃ (220.63 mg, 0.68 mmol) in DMF (2 mL) wasirradiated at 150° C. for 2 hrs. The resultant was partitioned betweenEtOAc (50 mL) and water (50 mL). To the aqueous layer was added NH₄Cl(until pH to 5) and the aqueous layer was extracted with EtOAc (5×50mL). The combined organic layers were washed with brine (3×50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The residue wasredissolved in EtOAc (100 mL), washed with brine (2×100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to provide crude5-[[(3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one(105 mg, 68% yield) as an orange-brown solid.

LC/MS: (ES⁺, Short): RT 2.08 min, m/z 571.3 [M+H]⁺

Step 9:

To a solution of5-[[(3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one (105 mg, 0.18 mmol) in EtOH (3 mL) was added aq. 1N HCl (4 mL, 4mmol) and the mixture stirred at 70° C. for 16 hrs. The mixture wasconcentrated in vacuo. The residue was dissolved in MeOH (5 mL)/DCM (50mL) and washed with sat. aq. Na₂CO₃ (25 mL). The aqueous layer waswashed with DCM (4×50 mL) and EtOAc (50 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (0-100% EtOAc/pet. Ether),reverse phase flash chromatography (20-60% MeCN/water/0.1% formic acid)and SCX-2 to provide5-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one(4.72 mg, 5% yield) as an off-white solid.

LCMS (ES⁺, Long): RT 3.01 min, m/z 441.1 [M+H]⁺

Chiral ee of enantiomer—96.8% [RT—7.70 mins]

¹H NMR (400 MHz, d₆-DMSO) δ: 12.84 (0.2H, br s), 12.52 (0.8H, s), 10.46(1H, m), 7.97 (1H, d, J=5.8 Hz), 7.84-7.62 (3H, m), 7.42-7.30 (3H, m),7.02 (2H, d, J=8.8 Hz), 6.80 (1H, d, J=2.9 Hz), 6.69 (1H, dd, J=8.8, 2.9Hz) 6.29 (1H, d, J=5.8 Hz), 5.39 (1H, d, J=7.0 Hz), 4.62 (1H, dd, J=2.5,11.6 Hz), 4.44 (1H, dd, J=8.3, 11.6 Hz), 2.91 (2H, t, J=7.7 Hz),2.56-2.51 (2H, m).

Example 20:5-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one

Prepared in a similar way to Example 19 using (2S)-oxiran-2-yl]methyl3-nitrobenzenesulfonate instead of (2R)-oxiran-2-yl]methyl3-nitrobenzenesulfonate.

LCMS (ES⁺, Long): RT 3.02 min, m/z 441.1 [M+H]⁺

Chiral ee of enantiomer 92.8% [RT 8.98 mins]

¹H NMR (400 MHz, d₆-DMSO) δ: 12.84 (0.2H, br s), 12.55 (0.8H, br s),10.46 (1H, s), 7.97 (1H, d, J=5.8 Hz), 7.82-7.63 (3H, m), 7.45-7.28 (3H,m), 7.02 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=2.8 Hz), 6.69 (1H, dd, J=2.8,8.8 Hz), 6.29 (1H, d, J=5.8 Hz), 5.42-5.33 (1H, m), 4.65-4.57 (1H, m),4.48-4.39 (1H, m), 2.91 (2H, t, J=7.7 Hz), 2.66-2.51 (2H, m).

Example 21:2-Methyl-4-[3-(5-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-pyridine

Step 1:

A mixture of 4-fluoro-2-methylpyridine (100 mg, 0.9 mmol),6-hydroxychromane-3-carboxylic acid (199.99 mg, 1.03 mmol) and Cs₂CO₃(678.01 mg, 2.08 mmol) in DMF (4 mL) was irradiated at 150° C. for 3hrs. The mixture was cooled. To the mixture was added Cs₂CO₃ (293.21 mg,0.9 mmol) and 2-bromoacetophenone (340 mg, 1.71 mmol). The mixture wasstirred for 3 hrs, diluted with EtOAc (120 mL), washed with water (50,30 mL), brine (30 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by flash column chromatography (0-100%EtOAc/Hept) to provide phenacyl 6-[(2-methyl-4-pyridyl)oxy]chromane-3-carboxylate (239 mg, 66% yield) as a brown oil.

LCMS (ES⁺, Short): RT 1.40 min, m/z 404.4 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ: 8.34 (1H, d, J=5.7 Hz), 7.96-7.91 (2H, m),7.68-7.63 (1H, m), 7.56-7.49 (2H, m), 6.93-6.91 (0.2H, m), 6.90-6.89(0.8H, m), 6.88-6.85 (1.7H, m), 6.85-6.84 (0.3H, m), 6.68-6.63 (2H, m),5.45 (2H, d, J=0.9 Hz), 4.64-4.57 (1H, m), 4.33-4.25 (1H, m), 3.33-3.20(2H, m), 3.18-3.10 (1H, m), 2.51 (3H, s).

Step 2:

A mixture of phenacyl 6-[(2-methyl-4-pyridyl)oxy]chromane-3-carboxylate(230 mg, 0.57 mmol) and NH₄OAc (4.39 g, 57.01 mmol) in AcOH (4 mL) washeated at 120° C. for 5 hrs. The reaction was cooled and added slowly tosat. aq. NaHCO₃ (150 mL) and stirred for 1 hr. The aqueous layer wasextracted with EtOAc (2×200 mL) and the combiped organic layers weredried (Na₂SO₄), filtered, concentrated in vacuo. The residue waspurified by flash column chromatography (0-5% MeOH/DCM), partitonedbetween DCM (50 mL)/sat. aq. NaHCO₃ (50 mL), the organic layer was dried(phase separator) and concentrated in vacuo to provide2-methyl-4-[3-(5-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-pyridine (29.3mg, 13% yield) as a light tan solid.

LCMS: (ES⁺, Long): RT 2.16 min, m/z 384.0 [M+H]⁺.

¹H NMR shows a mixture of confirmers:

¹H NMR (400 MHz, d₆-DMSO) δ: 12.31 (0.2H, br s), 12.10 (0.8H, br s),8.30 (1H, d, J=5.7 Hz), 7.77-7.73 (1.6H, m), 7.66-7.62 (0.4H, m), 7.60(0.8H, d, J=2.0 Hz), 7.43-7.38 (0.3H, m), 7.36-7.30 (1.7H, m), 7.28(0.2H, d, J=1.4 Hz), 7.26-7.21 (0.2H, m), 7.19-7.13 (0.8H, m), 7.04-7.00(1H, m), 6.95-6.88 (2H, m), 6.75 (1H, d, J=2.4 Hz), 6.69 (1H, dd, J=2.4,5.7 Hz), 4.55-4.49 (1H, m), 4.17-4.09 (1H, m), 3.45-3.36 (1H, m),3.30-3.20 (1H, m), 3.17-3.07 (1H, m), 2.40 (3H, s).

Example 22: Biological data

In vitro biological evaluation of compounds of the invention was carriedout following the procedure detailed below. The procedure providesbinding affinity data for the compounds of the invention againstB-RAFRAF^(V600E) and C-RAF. The binding affinity is shown in Table 4below.

LanthaScreen™ Eu kinase binding assay

To determine whether compounds bind to RAF kinases, they are tested in acompetition binding assay. The Invitrogen LanthaScreen™ Eu binding assayinvolves the binding of an Alexa-Fluor® 647-labelled, ATP-competitivekinase tracer to the kinase of interest. A Europium-labelled anti-tagantibody also binds to the kinase of interest. Simultaneous binding ofthe tracer and the antibody brings them into close proximity and uponexcitation at 340 nm, triggers fluorescence resonance energy transfer(FRET) between the Europium donor fluorophore on the antibody and theAlexa Fluor® 647 acceptor on the tracer. The dual emission signalproduced can be measured at 665 and 615 nm.

Compounds at a concentration of 3 mM are serially diluted (e.g. 10 μl,90 μl of 100% dimethyl sulfoxide (DMSO)) seven times in 96-well platesfor a total of 8 dilution points. Each DMSO dilution is further diluted1:100 in kinase buffer (e.g. 5 μl into 495 μl kinase buffer) containing50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35.

Each well in a 96-well Optiplate™ (Perkin Elmer 6005569) contains 30 μlof final volume per sample, including 10 μl compound at 3× the desiredconcentration, providing 10 μM at the final maximum concentration, 10 μlof kinase/antibody mixture at 3× the desired concentration of RAFrecombinant kinases and antibody providing 5 nM final concentration ofB-RAF^(V600E) kinase (Invitrogen PV3849) and 3 nM final concentration ofC-RAF Y340D/Y341D kinase (Invitrogen PV3805) and 2 nM finalconcentration of Eu-anti-GST antibody (PV5594), and 10 μl of 3× thedesired concentration of kinase tracer 178 (Invitrogen PV5593) providingfinal concentrations of 20 nM tracer for B-RAF^(V600E) kinase and 6 nMtracer for C-RAF kinase. The plates are incubated for 5 hours at roomtemperature and read on an EnVision plate reader (Perkin Elmer).

All data are analysed using the GraphPad Prism software package.Inhibition of tracer binding to the kinase of interest is assessed bydetermination of IC₅₀ value, which is defined as the concentration ofcompound which decreased the level of FRET signal measured at 665 nm by50%.

The results of the in vitro biological binding affinity study of thecompounds of the invention are given in Table 3 below. The compounds allshow binding affinity against B-RAF^(V600E) mutant and C-RAF. The tableshows the B-RAF^(V600E) and C-RAF inhibition activity of compounds ofthe invention categorised based on the IC₅₀ values, the categories being“+”, “++” and “+++”. The category “+” refers to compounds with an IC₅₀value of greater than 100 nM. The category “++” refers to compounds withan IC₅₀ value of 4 nM to 100 nM. The category “+++” refers to compoundswith an IC₅₀ value of less than 4 nM. Compounds having a designation of“+++” are thus more active against B-RAF^(V600E) and/or C-RAF thancompounds having a designation of “++”. Similarly, compounds having adesignation of “++” are more active against B-RAF and/or C-RAF thancompounds having a designation of “+”.

TABLE 4 BRAF^(V600E) CRAF Ex- binding binding ample Name affinityaffinity  1 5-[3-(1H-benzimidazol-2-yl)chroman-6-yl] +++ +++oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one  25-[3-(7-chloro-1H-benzimidazol-2-yl] ++ ++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  35-[3-(4-phenyl-1H-imidazol-2-yl)chroman- +++ +++6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  3A Enantiomer 1 of5-[3-(4-phenyl-1H-imidazol- +++ +++2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one]  3BEnantiomer 2 of 5-[3-(4-phenyl-1H-imidazol- +++ +++2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one]  45-[3[4-(4-pyridyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  55-[3-(4-tert-butyl-1H-imidazol-2-yl) ++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  65-[3-[4-(3-thienyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  75-[3-[4-(2-thienyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  85-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one  95-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 105-[3-[4-(benzofuran-3-yl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 115-[3-[5-(3-pyridyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 125-[3-[5-(4-methylsulfonylphenyl)-1H- + ++imidazol-2-yl]chroman-6-yl]oxy-3,4- dihydro-1H-1,8-naphthyridin-2-one 135-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl] +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 145-[3-[5-(1,3-benzodioxol-5-yl)-1H-imidazol- +++ +++2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 155-[3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)- ++ +++1H-imidazol-2-yl]chroman-6-yl]oxy-3,4- dihydro-1H-1,8-naphthyridin-2-one16 5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H- ++ +++chromen-6-yl]oxy]-3,4-dihydro-1H-1,8- naphthyridin-2-one 175-[3-(3-phenyl-1,2,4-oxadiazol-5-yl) ++ ++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 185-[3-(5-phenyl-1H-pyrazol-3-yl) +++ +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 195-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)- +++ +++2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one 205-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)- +++ +++2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one 212-Methyl-4-[3-(5-phenyl-1H-imidazol-2-yl) ++ ++chroman-6-yl]oxy-pyridine

Examples of compounds of the invention with values for their IC₅₀ aregiven in Table 5 below.

TABLE 5 BRAF^(V600E) CRAF binding binding Ex- affinity affinity ampleName IC₅₀ (nM) IC₅₀ (nM) 3 5-[3-(4-phenyl-1H-imidazol-2-yl) 0.8 0.6chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one] 3A Enantiomer 1of 5-[3-(4-phenyl-1H- 1.5 1.0 imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one] 3B Enantiomer 2 of 5-[3-(4-phenyl-1H-1.4 0.8 imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one] 65-[3-[4-(3-thienyl)-1H-imidazol-2-yl] 1.0 0.4chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one 75-[3-[4-(2-thienyl)-1H-imidazol-2-yl] 1.1 0.5chroman-6-yl]oxy-3,4-dihydro-1H-1,8- naphthyridin-2-one

Compounds of the invention were selected to be tested in an AlphaScreen®SureFire® pERK1/2 assay to assess the compounds cellular activity.

WiDr AlphaScreen® SureFire® pERK1/2 Cellular Assay

The human WiDr colorectal cell line endogenously expresses theB-RAF^(V600E) mutation, which leads to constitutive activation of theMAP kinase pathway and phosphorylation of ERK in the absence of ligands.To determine whether compounds inhibit constitutive ERK phosphorylationin WiDr cells, they are tested using AlphaScreen® SureFire® technology(Perkin Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K). On day 1, WiDrcells (ATCC CRL-218™) are counted, centrifuged and resuspended in growthmedia (Minimum essential medium containing 1 g/L D-glucose and 2 mML-glutamine (Gibco 31095), 10% fetal bovine serum (VWR S061)). The cellsare plated, 200 μl in each well of 96-well culture dish (Corning 3585)to a final cell density of 80,000 cells per well and incubated at 37° C.in 5% CO₂ overnight.

On day 2, compounds at a concentration of 6 mM are serially diluted 10μl into 90 μl of 100% dimethyl sulfoxide (DMSO) six times in 96-wellplates for a total of 7 dilution points. Each dilution and a DMSOcontrol are further diluted 1:200 (e.g. 5 μl into 995 μl minimumessential medium+0.1% fetal bovine serum). The media is removed and 100μl compound dilution or control in minimum essential medium+0.1% fetalbovine serum is added to triplicate wells containing cells, providing 30μM compound at the maximum concentration. The cells are treated for 1hour or 24 hours at 37° C. The treatment is then removed and the cellsare incubated with lysis buffer containing phosphatase inhibitors for 10minutes at room temperature. Cell lysates are transferred to a 96-wellOptiplate™ (Perkin Elmer 6005569) and incubated with anti-mouse IgGacceptor beads, a biotinylated anti-ERK1/2 rabbit antibody recognisingboth phosphorylated and non-phosphorylated ERK1/2, a mouse antibodytargeted to the Thr202/Tyr204 epitope and recognising phosphorylated ERKproteins only, and streptavidin-coated donor beads. The biotinylatedantibody binds to the streptavidin-coated donor beads and thephopsho-ERK1/2 antibody binds to the acceptor beads. Plates are read onan EnVision reader (Perkin Elmer) and excitation of the beads at 680 nmwith a laser induces the release of singlet oxygen molecules from thedonor beads that triggers energy transfer to the acceptor beads in closeproximity, producing a signal that can be measured at 570 nm. Bothantibodies bind to phosphorylated ERK proteins, bringing the donor andacceptor beads into close proximity.

All data are analysed using the GraphPad Prism software package.Inhibition of ERK phosphorylation is assessed by determination of IC₅₀value, which is defined as the concentration of compound which decreasedthe level of phosphorylated ERK proteins by 50%.

The results of WiDr AlphaScreen SureFire pERK1/2 cellular assay aregiven in Table 6 below. The compounds tested all showed activity withina cell. The activity of the compounds of the invention has beencategorised based on the IC₅₀ values, the categories being “+”, “++” and“+++” The category “+” refers to compounds with an IC₅₀ value of greaterthan 300 nM. The category “++” refers to compounds with an IC₅₀ value of70 nM to 300 nM. The category “+++” refers to compounds with an IC₅₀value of less than 70 nM.

TABLE 6 WiDr WiDr pERK pERK inhibition inhibition Ex- category categoryample Name 1 hr 24 hrs  3 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman- ++ +6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  3A Enantiomer 1 of5-[3-(4-phenyl- +++ + 1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one]  3B Enantiomer 2 of5-[3-(4-phenyl-1H- ++ + imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one] 195-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)- ++ +2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one 205-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)- ++ +2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one

Examples of compounds of the invention with values for their IC₅₀ aregiven in Table 7 below.

TABLE 7 WiDr WiDr pERK pERK inhibition inhibition Ex- IC₅₀ (nM) IC₅₀(nM) ample Name 1 hr 24 hrs 3 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-100 671 6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one] 3A Enantiomer 1of 5-[3-(4-phenyl-1H-  32 562 imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one] 3B Enantiomer 2 of 5-[3-(4-phenyl-1H-115 416 imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one]

A375 AlphaScreen SureFire pERK1/2 Cellular Assay

The human A375 malignant melanoma cell line endogenously expresses theB-RAF^(V600E) mutation, which leads to constitutive activation of theMAP kinase pathway and phosphorylation of ERK in the absence of ligands.To determine whether compounds inhibit constitutive ERK phosphorylationin A375 cells, they are tested using AlphaScreen® SureFire® technology(Perkin Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K). On day 1, A375cells (ATCC CRL-1619) are counted, centrifuged and resuspended in growthmedia (Dulbecco's modified Eagle's medium containing 4.5 g/L D-glucose(Gibco 41965), 10% fetal bovine serum (VWR S061) and 4 mM L-glutamine(Sigma G7513)). The cells are plated, 200 μl in each well of 96-wellculture dish (Corning 3585) to a final cell density of 60,000 cells perwell and incubated at 37° C. in 5% CO₂ overnight.

On day 2, compounds at a concentration of 6 mM are serially diluted 10μl into 90 μl of 100% dimethyl sulfoxide (DMSO) six times in 96-wellplates for a total of 7 dilution points. Each dilution and a DMSOcontrol are further diluted 1:200 (e.g. 5 μl into 995 μl serum-freegrowth media). The media is removed and 50 μl compound dilution orcontrol in serum-free media is added to triplicate wells containingcells, providing 30 μM compound at the maximum concentration. The cellsare treated for 30 minutes at room temperature. The treatment is thenremoved and the cells are incubated with lysis buffer containingphosphatase inhibitors for 10 minutes at room temperature. Cell lysatesare transferred to a 96-well Optiplate™ (Perkin Elmer 6005569) andincubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2rabbit antibody recognising both phosphorylated and non-phosphorylatedERK1/2, a mouse antibody targeted to the Thr202/Tyr204 epitope andrecognising phosphorylated ERK proteins only, and streptavidin-coateddonor beads. The biotinylated antibody binds to the streptavidin-coateddonor beads and the phopsho-ERK1/2 antibody binds to the acceptor beads.Plates are read on an EnVision reader (Perkin Elmer) and excitation ofthe beads at 680 nm with a laser induces the release of singlet oxygenmolecules from the donor beads that trigger energy transfer to theacceptor beads in close proximity, producing a signal that can bemeasured at 570 nm. Both antibodies bind to phosphorylated ERK proteins,bringing the donor and acceptor beads into close proximity.

All data are analysed using the GraphPad Prism software package.Inhibition of ERK phosphorylation is assessed by determination of IC₅₀value, which is defined as the concentration of compound which decreasedthe level of phosphorylated ERK proteins by 50%.

The results of AlphaScreen SureFire pERK1/2 cellular assay are given inTable 8 below. The compounds tested all showed activity within a cell.The activity of the compounds of the invention has been categorisedbased on the IC₅₀ values, the categories being “+”, “++” and “+++” Thecategory “+” refers to compounds with an IC₅₀ value of greater than 300nM. The category “++” refers to compounds with an IC₅₀ value of 70 nM to300 nM. The category “+++” refers to compounds with an IC₅₀ value ofless than 70 nM.

TABLE 8 A375 pERK Ex- inhibition ample Name category  25-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6-yl] ++oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one  35-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy- +++3,4-dihydro-1H-1,8-naphthyridin-2-one]  3A Enantiomer 1 of5-[3-(4-phenyl-1H-imidazol-2-yl) +++chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  3B Enantiomer2 of 5-[3-(4-phenyl-1H-imidazol-2-yl) ++chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  45-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6-yl] +oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one  65-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl] +++oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one  75-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6-yl] +++oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one 165-[[3-[4-phenyl-1H-imidazol-2-yl)-2H-chromen-6-yl] +oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one 185-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy- +3,4-dihydro-1H-1,8-naphthyridin-2-one 195-[[3S)-3-[4-phenyl-1H-imidazol-2-yl)-2,3-dihydro- ++1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8- naphthyridin-2-one 205-[[(3R)-3-[4-phenyl-1H-imidazol-2-yl)-2,3- ++dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro- 1H-1,8-naphthyridin-2-one

Examples of compounds of the invention with values for their IC₅₀ aregiven in Table 9 below.

TABLE 9 A375 pERK Ex- inhibition ample Name IC₅₀ (nM)  35-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-   9.83,4-dihydro-1H-1,8-naphthyridin-2-one]  3A Enantiomer 1 of5-[3-(4-phenyl-1H-imidazol-2-yl)  12.0chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  3B Enantiomer2 of 5-[3-(4-phenyl-1H-imidazol-2-yl) 112chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one]  65-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]  23.4oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one 195-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro- 1551,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8- naphthyridin-2-one 205-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro- 2821,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8- naphthyridin-2-one

IPC-298 AlphaScreen SureFire pERK1/2 Cellular Assay

The human IPC-298 melanoma cell line endogenously expresses theNRAS^(Q61L) mutation leading to constitutive activation of the MAPKpathway and phosphorylation of ERK via C-RAF in the absence of ligands.To determine whether compounds inhibit C-RAF-mediated ERK activation inB-RAF^(WT) IPC-298 cells, they are tested using AlphaScreen® SureFire®technology (Perkin Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K). On day1, IPC-298 cells (DSMZ ACC-251) are counted, centrifuged and resuspendedin growth medium (RPMI 1640 containing 2 g/L D-glucose (Gibco 31870),10% fetal bovine serum (VWR S061) and 2 mM L-glutamine (Sigma G7513).The cells are plated, 100 uL in each well of 96 well culture dish(Corning 3585) to a final cell density of 40,000 cells per well andincubated at 37° C. in 5% CO₂ overnight.

On day 2, compounds at a concentration of 6 mM are serially diluted 5 μlinto 45 μl of 100% dimethyl sulfoxide (DMSO) six times in 96-well platesfor a total of 7 dilution points. Each dilution and a DMSO control arefurther diluted 1:200 (e.g. 5 μl into 995 μl serum-free RPMI 1640medium). The media is removed and 100 μl compound dilution or control inserum-free RPMI 1640 medium is added to triplicate wells containingcells, providing 30 μM compound at the maximum concentration. The cellsare treated for 1 hour at 37° C. in 5% CO₂. The treatment is thenremoved and the cells are incubated with lysis buffer containingphosphatase inhibitors for 10 minutes at room temperature with gentleshaking. Cell lysates are transferred to a 96-well Optiplate™ (PerkinElmer 6005569) and incubated with anti-mouse IgG acceptor beads, abiotinylated anti-ERK1/2 rabbit antibody recognising both phosphorylatedand non-phosphorylated ERK1/2, a mouse antibody targeted to theThr202/Tyr204 epitope and recognising phosphorylated ERK proteins only,and streptavidin-coated donor beads. The biotinylated antibody binds tothe streptavidin-coated donor beads and the phopsho-ERK1/2 antibodybinds to the acceptor beads. Plates are read on an EnVision reader(Perkin Elmer) and excitation of the beads at 680 nm with a laserinduces the release of singlet oxygen molecules from the donor beadsthat triggers energy transfer to the acceptor beads in close proximity,producing a signal that can be measured at 570 nm. Both antibodies bindto phosphorylated ERK proteins, bringing the donor and acceptor beadsinto close proximity.

All data are analysed using the GraphPad Prism software package.Activation of ERK phosphorylation is expressed as a percentage ofactivation relative to the reference compound, Dabrafenib.

A representative example of the results of IPC-298 AlphaScreen SureFirepERK1/2 cellular assay is given in FIG. 1 . Example 3(5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2 -one]) shows reduced paradoxicalactivation of MAPK pathway in comparison to Dabrafenib.

In total nine compounds of the invention were tested in the IPC-298AlphaScreen SureFire pERK1/2 cellular assay. The compounds were examples3, 3A, 3B, 4, 6, 7, 18, 19 and 20. Each compound yielded similar resultsto that of FIG. 1 and showed reduced paradoxical activity

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed. The reader'sattention is directed to all papers and documents which are filedconcurrently with or previous to this specification in connection withthis application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: the bond betweenY and Z is a single bond or a double bond; A is a phenyl ring; R¹ is asubstituted or unsubstituted heterocyclic moiety which either contains 5or 6 atoms in a single ring or 8, 9, 10 or 11 atoms in a fused bicyclicring system, when substituted R¹ contains 1 to 4 substituentsindependently selected from the group consisting of halo, —OR^(A),—NR^(A)R^(B), ═O, —OC(O)R^(C), —C(O) R^(C), —C(O)OR^(A),—NR^(A)C(O)R^(C), —C(O)NR^(A)R^(B), —SO₂R^(C), —SOR^(C),—NR^(A)SO₂R^(C), —SO₂NR^(A)R^(B), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl andC₃₋₆ cycloalkyl; X is O; Y is —CHW and the bond between Y and Z is asingle bond; or Y is —CW and the bond between Y and Z is a double bond;W represents -het¹-R³ or -het², in which het¹ is an optionally furthersubstituted five or six membered cycloalkyl ring or heterocyclic ring,and het² is a carbocyclic or heterocyclic ring system containing 8, 9 or10 atoms in a fused bicyclic ring system; in which het² is unsubstitutedor substituted; and het¹, when further substituted, and het² whensubstituted contain 1 or 2 substituents independently selected at eachoccurrence from halo, —OR^(A), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, in which the aforementioned alkyl, haloalkyl and cycloalkylgroups are themselves unsubstituted or substituted with 1 to 3 groupsindependently selected from the group consisting of —OR^(A), —CN, and—NR^(A)R^(B); Z is O, or —CH₂ and the bond between Y and Z is a singlebond: or Z is —CH and the bond between Y and Z is a double bond; R^(2A)is selected from the group consisting of H, halo, —OR^(A), —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl; R³ is selected from the groupconsisting of substituted or unsubstituted: C₁₋₆ alkyl, C₁₋₆ haloalkyl,a carbocyclic moiety or a heterocyclic moiety, wherein the carbocyclicmoiety and heterocyclic moiety either contain 5 or 6 atoms in a singlering or 8, 9 or 10 atoms in a fused bicyclic ring system, and whensubstituted R³ contains 1 to 4 substituents independently selected fromthe group consisting of halo, —OR^(A), —NR^(A)R^(B), —SO₂R^(C),—SOR^(C), CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl in which theaforementioned alkyl, haloalkyl and cycloalkyl groups are themselvesunsubstituted or substituted with 1 to 3 groups independently selectedfrom the group consisting of —OR^(A), —CN, —SOR^(C) and —NR^(A)R^(B);R^(A) and R^(B) are each independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; and R^(C) is selectedfrom the group consisting of C₁₋₄ alkyl and C₁₋₄ haloalkyl.
 2. Thecompound of claim 1, wherein Z is O; and Y is —CHW.
 3. The compound ofclaim 1, wherein Z is —CH₂; and Y is —CHW.
 4. The compound of claim 1,wherein Z is —CH; and Y is —CW.
 5. The compound of claim 1, wherein R¹is a substituted or unsubstituted heterocyclic moiety which eithercontains 6 atoms in a single ring or 10 atoms in a fused bicyclic ringsystem.
 6. The compound of claim 1, wherein R¹ is selected from thegroup consisting of substituted or unsubstituted: pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, quinolinyl, tetrahydroquinolinyl,dihydroquinolinyl, quinolinone-yl, tetrahydroquinolinone-yl,dihydroquinolinone-yl, isoquinolinyl, tetrahydroisoquinolinyl,dihydroisoquinolinyl, isoquinolinoneyl, tetrahydroisoquinolinone-yl,dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl,dihydronappthyridinyl, tetrahydronaphthyridinyl,oxo-tetrahydronaphthyridinyl, and oxo-dihydro-H-naphthyridinyl.
 7. Thecompound of claim 6, wherein R¹ is substituted or unsubstituted pyridylor substituted or unsubstituted oxodihydro-H-naphthyridinyl.
 8. Thecompound of claim 1, wherein W represents -het¹-R³ or -het², whereinhet¹ is represented by a group selected from the group consisting ofsubstituted or unsubstituted: C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl andC₅₋₆ heteroaryl, and het² is represented by a group selected from thegroup consisting of substituted or unsubstituted: C₈₋₁₀ cycloalkyl, C₁₀aryl, C₈₋₁₀ heterocycloalkyl and C₈₋₁₀ heteroaryl.
 9. The compound ofclaim 1, wherein het¹ is represented by substituted or unsubstituted:pyrazole, imidazole or oxadiazole; and het² is represented bysubstituted or unsubstituted benzimidazole.
 10. The compound of claim 1,wherein R³ is selected from the group consisting of C₁₋₆ alkyl, asubstituted or unsubstituted carbocyclic moiety or a substituted orunsubstituted heterocyclic moiety, wherein the carbocyclic moiety andheterocyclic moiety either contain 5 or 6 atoms in a single aromaticring or 8, 9 or 10 atoms in a fused bicyclic ring system, wherein onering of the bicyclic ring system is aromatic.
 11. The compound of claim10, wherein R³ is selected from the group consisting of a substituted orunsubstituted: iso-propyl, tert-butyl, phenyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, indolinyl, isoindolinyl, benzodioxanyl,benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl,benzodioxolanyl, indazolyl, indazolinyl, benzimidazolyl,benzimidazolinyl, benzthiazolyl, benzoisothiazol, chromanyl,isochromanyl, tetralinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl andtetrahydroquinoxalinyl.
 12. The compound of claim 1, wherein R^(A) andR^(B) are each independently H, methyl, ethyl or trifluoromethyl; andR^(C) is methyl, ethyl or trifluoromethyl.
 13. The compound of claim 12,wherein R^(A) and R^(B) are H; R^(A) and R^(B) are methyl; or R^(A) is Hand R^(B) is methyl and R^(C) is methyl.
 14. The compound of claim 1,wherein the compound of formula (I) is selected from the groupconsisting of:


15. The compound of claim 14, wherein a * symbol indicates a chiralcentre; and the chiral centre relates to a single enantiomer that haseither a (R)-configuration or a (S)-configuration.
 16. The compound ofclaim 1, wherein the compound is a pharmaceutically acceptable saltthereof.
 17. A method of treatment of a condition which is modulated byRAF kinases, wherein the condition is selected from the group consistingof cancer, sarcoma, melanoma, skin cancer, haematological tumors,lymphoma, carcinoma and leukemia, wherein the method comprisesadministering to a patient in need thereof a therapeutic amount of acompound of formula (I):

wherein: the bond between Y and Z is a single bond or a double bond; Ais a phenyl ring; R¹ is a substituted or unsubstituted heterocyclicmoiety which either contains 5 or 6 atoms in a single ring or 8, 9, 10or 11 atoms in a fused bicyclic ring system, when substituted R¹contains 1 to 4 substituents independently selected from the groupconsisting of halo, —OR^(A), —NR^(A)R^(B), ═O, —OC(O)R^(C), —C(O)R^(C),—C(O)OR^(A), —NR^(A)C(O)R^(C), —C(O)NR^(A)R^(B), —SO₂R^(C), —SOR^(C),—NR^(A)SO₂R^(C), —SO₂NR^(A)R^(B), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl andC₃₋₆ cycloalkyl; X is O; Y is —CHW and the bond between Y and Z is asingle bond; or Y is —CW and the bond between Y and Z is a double bond;W represents -het¹-R³ or -het², in which het¹ is an optionally furthersubstituted five or six membered cycloalkyl ring or heterocyclic ring,and het² is a carbocyclic or heterocyclic ring system containing 8, 9 or10 atoms in a fused bicyclic ring system; in which het² is unsubstitutedor substituted; and het¹, when further substituted, and het² whensubstituted contain 1 or 2 substituents independently selected at eachoccurrence from halo, —OR^(A), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, in which the aforementioned alkyl, haloalkyl and cycloalkylgroups are themselves unsubstituted or substituted with 1 to 3 groupsindependently selected from the group consisting of —OR^(A), —CN, and—NR^(A)R^(B); Z is O, or —CH₂ and the bond between Y and Z is a singlebond: or Z is —CH and the bond between Y and Z is a double bond; R^(2A)is selected from the group consisting of H, halo, —OR^(A), —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl; R³ is selected from the groupconsisting of substituted or unsubstituted: C₁₋₆ alkyl, C₁₋₆ haloalkyl,a carbocyclic moiety or a heterocyclic moiety, wherein the carbocyclicmoiety and heterocyclic moiety either contain 5 or 6 atoms in a singlering or 8, 9 or 10 atoms in a fused bicyclic ring system, and whensubstituted R³ contains 1 to 4 substituents independently selected fromthe group consisting of halo, —OR^(A), —NR^(A)R^(B), —SO₂R^(C),—SOR^(C), —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl in which theaforementioned alkyl, haloalkyl and cycloalkyl groups are themselvesunsubstituted or substituted with 1 to 3 groups independently selectedfrom the group consisting of —OR^(A), —CN, —SOR^(C) and —NR^(A)R^(B);R^(A) and R^(B) are each independently selected from H, C₁₋₄ alkyl andC₁₋₄ haloalkyl; and R^(C) is selected from C₁₋₄ alkyl and C₁₋₄haloalkyl.
 18. The method of claim 17, wherein the condition treatableby the inhibition of Raf kinases is the group consisting of Barret'sadenocarcinoma; biliary tract carcinomas; breast cancer; cervicalcancer; cholangiocarcinoma; central nervous system tumors; primary CNStumors; glioblastomas, astrocytomas; glioblastoma multiforme;ependymomas; seconday CNS tumors (metastases to the central nervoussystem of tumors originating outside of the central nervous system);brain tumors; brain metastases; colorectal cancer; large intestinalcolon carcinoma; gastric cancer; carcinoma of the head and neck;squamous cell carcinoma of the head and neck; acute lymphoblasticleukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes;chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin'slymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia;hepatocellular carcinoma; lung cancer; small cell lung cancer; non-smallcell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer;pituitary adenoma; prostate cancer; renal cancer; metastatic melanomaand thyroid cancers.
 19. The method of claim 17, wherein the conditionis colorectal cancer or melanoma.
 20. The method of claim 17, furthercomprising administering simultaneously, sequentially or separately atherapeutic amount of an anti-tumour agent.
 21. A pharmaceuticalcomposition, wherein the composition comprises a compound of claim 1;and one or more pharmaceutically acceptable excipients.
 22. The compoundof claim 1, wherein the compound of formula (I) is


23. The compound of claim 1, wherein the compound of formula (I) is


24. The compound of claim 1, wherein the compound of formula (I) is